bluuebunny/crossref_metadata_2025 huggingface dataset:
Epidemiology, survival and new treatment modalities for intrahepatic cholangiocarcinoma (IHCC).
Authors: Wang Yating , Alsaraf Yasir , Bandaru Sai Samyuktha , Lyons Susan Elizabeth , Reap Leo Edward , Yu Zhiyong , Yu Qian
Published: July 2024

e16217

Background: Intrahepatic cholangiocarcinoma (IHCC), a rare biliary tract cancer, has been rising in incidence and is associated with poor survival. With the advent of new treatment modalities and various ongoing research, population-based perspective can be helpful to reflect the progress in managing this deadly disease and provide updated outcome information as a reference for comparison during upcoming clinical studies. We would like to provide a 20-year update on incidence and survival with reference to landmark trials, with a focus on survival outcomes of the recent 5 years for future insights. Recent and ongoing clinical trials will be discussed. Methods: This study extracted population data from the Surveillance, Epidemiology, and End Results (SEER) database. Age-adjusted incidence rate (AAIRs) and survival rate (SR) trends were calculated from January 2000 to December 2020 using 22 registries for the US population. Incidence and survival rates were collected from the SEER database, reported per 100,000 population and age adjusted to the 2020 US standard population. The annual percent change (APC) was used to report long term trends. Results: In this analysis of 19,948 IHCC patients, the AAIR increased from 0.49 per 100,000 in 2000 to 1.38 in 2020 (APC 6.94, 95% CI 6.32 to 7.56), with a notable decline from 2019 to 2020. Incidence rates overall displayed an uptrend course across subgroups divided by sex, race, age, and disease stage. The age-adjusted mOS climbed from 5.28 months in 2000 to 9.3 months in 2013, maintaining between 8.0-9.0 months after 2013. Using 2010 as a cutoff, when the ABC-02 trial was published, the decade-based mOS increased from 6.55 in 2000-2010 to 9.06 in 2010-2020, which remained statistically significant at 1-year, 3-year, and 5-year OS. During 2015-2020, the overall mOS was 8.8 months, with mOS of 24.3 months, 12.1 months, and 5.4 months for local, regional, and distant stages, respectively. Conclusions: These results indicate a steady rise in IHCC incidence since 2000, consistent across all subgroups. Survival rates have improved since 2000 but stabilized after 2013, following the publication of the ABC-02 trial published in 2010, which used systemic gemcitabine and cisplatin for unresectable iHCC. Updated survival data from 2015 onwards will serve as a reference of comparison for forthcoming clinical trials.
Associations between radiomic phenotypes and genomic mechanisms in HBV-associated cholangiocarcinoma.
Authors: Jia Yunlu , Wan Mingyu , Shen Yifei , Ruan Jian
Published: July 2024

e16249

Background: Despite the epidemiological association between cholangiocarcinoma (CCA) and HBV infection, little is known about the relevant oncogenic biomarkers for advancing cancer research and improving future patient therapy. Radiomics-based non-invasive biomarkers are promising to facilitate the translation of therapeutically related molecular subtypes for treatment allocation of patients with HBV-infected CCA. Methods: In this study, we included 55 CCA patients with whole-genome multi-omics data, proteomic data with matched magnetic resonance imaging (MRI) data from institute 1. A total of 431 patients with histopathological confirmed CCA (143 HBV-positive and 288 HBV-negative patients) were retrospectively enrolled from three institutes, and patients were allocated to the training (n = 302) and validation (n = 129) cohorts from different institutes or time period (7:3). Utilizing linear regression and gene set enrichment analysis, we identified statistically significant associations between radiomic imaging and various genomic features in HBV-positive or HBV-negative CCA patients. Additionally, we employed a random forest classifier based on radiomic features to predict the status of HBV infection, HBV-related gene mutations and protein expression profiling, and tested on an internal and an external CCA cohort (n = 53). Results: The analysis revealed significant and widespread associations between genomic features (somatic mutations, transcriptional activities and copy number variations) and radiomic features characterizing HBV infection status. Our results show that quantitative image features are capable of distinguishing several molecular phenotypes. We obtained significant predictive performance for HBV+ (AUC = 0.73), CA-199(AUC = 0.77) and NeuroInvasion (AUC = 0.71), activation of ESRP1(AUC = 0.79) and mutation of HNRNPUL2/MUC4 (AUC = 0.73). We externally validated the HBV prediction model (AUC = 0.76) on the internal and external cohort. The sensitivity, specificity, and accuracy were all > 70%. The radiomic signature succeeded to stratify patients into distinct survival outcomes according to HBV status, and remained an independent prognostic factor in multivariable analysis (DFS, P < 0.0001; OS, P = 0.029). Integrating the radiomic signature with clinicopathological-radiographic factors further improved prediction performance. A nomogram incorporating significant pathological predictors (HBV, CA-125, CA-199, Neuro invasion, peritoneal invasion, pT stage, pN stage, and differentiation, grade) and radiomics signatures displayed good prediction performance in estimating OS with AUC values of 0.895, 0.935, and 0.907 at 1, 3, and 5 years, respectively. Conclusions: This deep learning-driven combined radiomics model may provide as a useful tool to preoperatively predict HBV infection and improve therapeutic management of ICC patients.
Effect of malnutrition on cirrhotic patients with hepatocellular carcinoma: A nationwide study.
Authors: Obeidat Adham , Mansour Nour , Mahfouz Ratib , Aldiabat Mohammad
Published: July 2024

e16250

Background: Liver cancer is the sixth most common cancer and the third leading cause of cancer mortality worldwide. There are two main types of primary liver cancers; hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma. HCC accounts for around 80% of primary liver cancer cases. Generally, HCC develops in genetically susceptible individuals with risk factors, especially in the presence of cirrhosis. Cirrhosis is a systemic disease, and malnutrition is a key feature as well as an important complication which can be associated with worse outcomes. In this study, we aim to characterize the potential effects of malnutrition on HCC patients with underlying cirrhosis. Methods: The United States Nationwide Inpatient Sample (NIS) was used to extract hospitalization data of patients admitted between 2016 to 2018. Using ICD10 revision codes, we identified adults with the diagnosis of cirrhosis who have HCC with concomitant malnutrition, including sarcopenia. The control group included cirrhotic HCC patients without malnutrition. The primary outcome was the in-hospital mortality. Secondary outcomes included encephalopathy, ascites, variceal bleed, hepatorenal syndrome (HRS) and length of stay (LOS). Multivariate logistic regression was used to adjust for relevant variables. Results: We identified 423,158 patients admitted with cirrhosis. 20,582 had HCC, and of those, 2560 patients had the diagnosis of malnutrition. In this group of patients, the mean age was 59.85 years. 30% were females and 62% were Caucasians. When adjusted to other relevant variables, malnutrition was associated with increased in-hospital mortality (OR 1.40; P-value 0.000). It was also associated with an increased chance of developing encephalopathy (OR 1.42; P-value 0.000), ascites (OR 1.62; P-value 0.000), and HRS (OR 1.33; P-value 0.000). Moreover, it was associated with increased LOS (OR 1.99; P-value 0.001). Other factors associated with increased in-hospital mortality in cirrhotic HCC patients are described in the table. Conclusions: Malnutrition is a common complication in patients with cirrhosis. If identified, it can be treated efficiently. In this study, cirrhotic HCC patients with malnutrition had an increased chance of mortality. Further, they were at increased risk for cirrhosis decompensation and other in-hospital complications, which in turn can lead to increased LOS and therefore increased financial burden. We recommend that clinicians pay attention to patients with malnutrition and to treat them in order to prevent these complications. [Table: see text]
Integrating pathomics and radiomics for predicting survival among patients with intrahepatic cholangiocarcinoma undergoing surgical resection.
Authors: Wan Mingyu , Shen Yifei , Xu Nong , Ruan Jian
Published: July 2024

e16255

Background: Intrahepatic cholangiocarcinoma (ICC) is characterized by a high degree of malignancy and poor prognosis. Surgical resection remains the primary curative approach for this type of cancer. However, there is a lack of effective predictive tools for patients undergoing such treatments. Methods: In this study, we employed a random forest algorithm to develop our predictive model, which was rigorously validated through a ten-fold cross-validation method. The model leveraged the five most pertinent features extracted from the radiomics dataset to generate predictions. Subsequently, these predictive outcomes were utilized to discern and analyze the distinctions among features within the proteomics dataset to uncover the intricate associations between radiomic signatures and proteomic profiles. Results: In this study, a radiomics prognostic model based on MRI data (n = 150) was developed using a random forest algorithm, and validated using ten-fold cross-validation, achieving an AUC of 0.709. Subsequently, a similar approach was applied to construct a pathology-based model (n = 150), which resulted in an AUC of 0.815. The integration of proteomic and radiomic models reveals that the upregulation of VNN1 and the downregulation of SCGN are significantly associated with prognosis, suggesting a group of highly interactive proteins that may play key roles in the biological process under study. Conclusions: The integration of these omics models is beneficial for predicting the prognosis of ICC patients post-surgery.
First-line treatment patterns among patients with metastatic pancreatic ductal adenocarcinoma in the real-world setting.
Authors: Dennen Syvart , Harton Joanna , Cockrum Paul , Kim George P. , MacEwan Joanna P.
Published: July 2024

e16320

Background: Treatment options for patients (pts) with metastatic pancreatic ductal adenocarcinoma (mPDAC) have historically been limited. FOLFIRINOX (FFX) and gemcitabine + nab-paclitaxel (GnP) are both recommended first line (1L) treatments that have shown efficacy vs. gemcitabine monotherapy in clinical trials. More recently, small subgroups of pts have benefitted from regimens that include irinotecan liposome injection, targeted therapies, and checkpoint inhibitors (CPIs). To better understand treatment patterns in current practice, we examined the distribution of 1L therapies in a RW cohort of mPDAC pts diagnosed between 2015 and 2022. Methods: This retrospective observational study utilized the Ontada Clinical Data View: Pancreatic Cancer database. Adult pts diagnosed with mPDAC between November 2018 and November 2022 who initiated 1L treatment within 90 days of their diagnosis for metastatic disease were included in the study. Regimens were grouped into the following categories: FFX, GnP, gemcitabine monotherapy, FOLFOX, FOLFIRI, capecitabine/5-FU monotherapy, irinotecan liposome injection-containing regimens, CPI monotherapy, PARP inhibitors and other targeted therapy-containing regimens, no 1L, and other regimens (comprised of combinations of FFX and GnP components as well as other chemotherapeutic agents). Results: Of the 5,358 pts eligible for inclusion in the study, the majority received GnP (33%, 1,785 pts) or FFX (23%, 1,254 pts) in 1L. The next largest segment of pts did not receive 1L therapy (23%, 1,229 pts). Just 6% (345 pts) received gemcitabine monotherapy. The remaining 14% of pts received therapies other than the three primary 1L mPDAC treatments: 4% (207 pts) received FOLFOX, 2% (109 pts) received capecitabine/5-FU monotherapy, 2% (96 pts) received an irinotecan liposome injection-containing regimen, 0.7% (39 pts) received FOLFIRI, 0.5% (28 pts) received CPI monotherapy, and 0.5% (26 pts) received PARP inhibitors or other targeted therapies. 4% (240 pts) received various other chemotherapy combinations (comprised of combinations of FFX and GnP components and a small number of other chemotherapeutic agents, with ≤40 pts per combination). FFX pts were the youngest, with a mean age of 64yrs, compared to 70yrs for gemcitabine + nab-paclitaxel (p < .001). Gemcitabine monotherapy pts were the oldest (mean = 73yrs, p < .001 vs. GnP) and were more likely to have metastatic disease and an ECOG ≥2 (p < .001 vs. GnP). Conclusions: There are limited 1L treatment options for mPDAC. Since the and PRODIGE and MPACT trials, FFX, GnP, or gemcitabine monotherapy have been the primary recommended 1L treatments for most pts with mPDAC. While recent years have seen an increase in the availability of targeted and CPI therapies appropriate for small subgroups of mPDAC pts, in a RW sample, almost all pts received one of the three standard therapies.
Chemotherapy with or without surgery for locally advanced or borderline resectable pancreatic ductal adenocarcinoma: A retrospective multicenter international study.
Authors: Venerito Marino , Zhang Danmei , Becht Selina , Schütz Juliane , Steup ChristophDaniel , Bankstahl Ulli Simone , Habibzada Timorshah , Sadeghlar Farsaneh , De Scordilli Marco , Ongaro Elena , Krug Sebastian , Gonzalez-Carmona Maria A , Goetze Thorsten , Finkelmeier Fabian , Ettrich Thomas Jens , Cannizzaro Renato , Dorman Klara , Franck Caspar
Published: July 2024

e16352

Background: Current clinical guidelines recommend surgery for patients with locally advanced (LA)/borderline resectable (BR) pancreatic ductal adenocarcinoma (PDAC) who achieve disease control after induction therapy. However, the additional survival benefit of surgery in these patients is unknown. Methods: In this multicenter international retrospective cohort study, consecutive patients with BR/LA PDAC who achieved disease control after three to six months of induction therapy (combination chemotherapy or chemoradiotherapy) between January 2014 and July 2021 were retrospectively identified at 8 centers in Germany and Italy. Resectability status was determined by consensus in a multidisciplinary tumor board based on imaging findings, serum CA19-9, performance status and clinical response. Patient characteristics, progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Cox regression analysis was used to compare survival data. Results: A total of 138 patients who achieved disease control with induction therapy were analyzed. The median age at diagnosis was 66 years (range 45-82) and 43% of patients were female. 73 patients underwent surgery and 65 patients did not (median age 64 and 69 years, respectively, p = 0.02). Median OS was 20.0 months (95%CI 16.1-23.8) in the surgery group and 18.0 months (95%CI 13.6-22.4) in the nonsurgery group (hazard ratio for death, 0.90; 95%CI, 0.63 to 1.29, p = 0.57). Median PFS was 14.0 months (95%CI 8.9-19.1) in the surgery group and 15.0 months (95%CI 11.7-18.3) in the nonsurgery group (hazard ratio for disease progression, 1.04; 95%CI, 73 to 1,47, p = 0.83). The 2-year survival rates in the surgery and nonsurgery groups were 32.9% and 40.0%, respectively, with an overall odds ratio of 0.74 (95% CI: 0.37-1.47). Conclusions: In our multicenter international retrospective analysis, additional surgery did not confer a survival advantage to patients with BR/LA PDAC who achieved disease control with induction therapy.
Early prediction of pancreatic cancer through detection of methylated circulating DNA in blood.
Authors: Lin Ruo-Kai
Published: July 2024

e16353

Background: Pancreatic cancer represents a significant oncological challenge, contributing markedly to cancer-associated mortalities. This is attributed to the asymptomatic nature of early-stage disease, its inherently aggressive phenotype, and a notably suboptimal response to existing systemic therapies. Hence, the formulation of efficacious early diagnostic modalities for pancreatic cancer amenable to surgical resection is imperative to augment patient prognoses and enhance survival outcomes. Methods: The Infinium MethylationEPIC v2.0 BeadChip platform facilitated the examination of methylation profiles within plasma samples, while the HumanMethylation450 BeadChip array was employed for analogous analyses in corresponding tissue specimens from Taiwanese pancreatic cancer cohorts, aiding in gene selection. Subsequent methylation status verification was conducted via quantitative Methylation-Specific PCR (qMSP) on both genomic DNA and circulating cell-free DNA samples. For external methylation confirmation within a Western demographic, data from The Cancer Genome Atlas (TCGA) Portal were utilized, with further validation conducted using plasma samples from U.S. pancreatic cancer patients. Total 105 plasma from pancreatic cancer patients and healthy subjects were analyzed to calculate the candidate the accuracy, sensitivity, specificity of biomarkers for predict the pancreatic cancer. Results: The test exhibited an accuracy of 90.4%, sensitivity of 92.3%, and specificity of 90.1% in the detection of pancreatic cancer. Detection levels increased from 0% in healthy individuals to 87.5% in Stage I and 100% in Stages II, III, and IV. The CA19-9 marker displayed limited specificity with a high rate of false positives. Moreover, the test dynamically evaluated tumor burden by monitoring circulating methylated ZFP30 and FBXL7 in the plasma of breast cancer patients post-treatment. Conclusions: The analysis of plasma for methylated ZFP30 and FBXL7 provides an innovative and accurate noninvasive method that outperforms the existing blood biomarker CA19-9 for the prediction and ongoing assessment of tumor burden following treatment in pancreatic cancer.
ctDNA for clinical decision support in pancreatic cancer.
Authors: ASCHERMAN BENJAMIN , Amini Neda , Koti Shruti , King Daniel
Published: July 2024

e16354

Background: Circulating tumor DNA (ctDNA) is increasingly used to inform therapeutic decisions and its applicability to pancreatic cancer is emerging. We explore the adoption of ctDNA profiling in patients presenting to our pancreatic cancer clinic to help guide localized and metastatic pancreatic cancer treatment. Methods: This was an IRB-approved retrospective cohort study of Signatera ctDNA profiling among patients with pancreatic cancer at Northwell Health between October 2021 and September 2023. Patients received ctDNA testing at various treatment timepoints and were categorized according to clinical context: neoadjuvant, adjuvant, surveillance, radiographic relapse, and metastatic. Average ctDNA level and conversion rates were calculated for each group. Results: There were 203 tests completed among 59 patients representing the following clinical contexts: 36% metastatic disease, 27% in the adjuvant setting, 23% during surveillance, 7% prior to surgery, and 6% after relapse. 43 patients had ctDNA tests that were drawn but were cancelled or could not be performed due to inadequate tissue samples, of which 8 had at least one completed test and were included in final analysis. Of all 27 metastatic patients, 8 patients had tests that were never completed. 46% of all tests were positive, which ranged from 0.3 to 8089 MTM/mL, and averaged 196 MTM/mL. 51% of all patients had ctDNA results that remained positive, 34% remained negative, and 15% changed over time from either positive to negative or vice versa. Median ctDNA level was 0.1 MTM/mL or less for patients who were tested prior to surgery or during adjuvant treatment or surveillance and the median ranged from 0.0-67.1 for patients with metastatic disease or relapse. All ctDNA tests sent after radiographic relapse also tested positive. Conclusions: ctDNA testing was most commonly performed in patients with localized disease on adjuvant chemotherapy, and in those with metastatic disease at time of diagnosis, who also had the highest rates of positive tests by stage at diagnosis. Given all patients tested during relapse had positive tests, ctDNA may be an early predictor of disease progression in patients with negative tests on surveillance. When tissue is limited, such as in metastatic patients who are less likely to undergo surgery, production of the ctDNA assay may be hindered. A prospective, larger scale, and more longitudinal study would add greater power and clinical context.
Development of a multi-analyte blood test for the early detection of pancreatic ductal adenocarcinoma (PDAC) and performance compared to CA19-9.
Authors: Athanasiou Alcibiade , Kureshi Natasha , Palma Norma Alonzo , Schiess Ralph , King Thomas C.
Published: July 2024

e16360

Background: Early detection of PDAC can improve survival but is hampered by the lack of recognizable symptoms in early disease. Imaging has been the mainstay for surveillance of high-risk individuals but has proven to be cumbersome and may lack sensitivity to detect small tumors. CA19-9 is the only available blood biomarker for PDAC, but it is neither sensitive nor specific enough for it to be recommended for high-risk surveillance. A sensitive and specific blood biomarker for PDAC could positively impact this situation. Methods: Serum samples from patients across multiple centers with stage I and II PDAC (n = 75) and matched controls at high risk for PDAC (genetic and familial) (n = 83) were assessed for more than 2,900 protein analytes using O-link multiplex technology and conventional immunoassays for selected protein candidates. Machine learning was used to combine the biomarker candidates to create 4-plex signatures discriminating PDAC and controls. Results: ROC (receiver operating characteristic) curve analysis of these revealed signatures with performance superior to CA19-9 and a previously commercially available assay, IMMRay PanCan-d (AUC of 0.97 and 0.94 vs. 0.87 for CA19-9 and 0.88 for IMMRay). A subset of these candidate biomarkers has now been transitioned to standardized ELISA assays which are being used to construct a final signature for clinical validation in an independent set of PDAC and high-risk control samples. Conclusions: A novel multi-analyte blood test utilizing newly-discovered PDAC biomarkers has the potential to improve early detection of PDAC in high-risk individuals.
Laparoscopic versus open pancreatoduodenectomy for periampullary tumors: An updated systematic review and meta-analysis.
Authors: Bittar Vinicius , Reis Pedro Cotta Abrahão , Almirón Giulia , Schramm Ana Júlia , Oliveira João Pedro , Cagnacci Renato , Camandaroba Marcos Pedro Guedes
Published: July 2024

e16362

Background: Laparoscopic pancreatoduodenectomy (LPD) has emerged as an alternative to open technique in treating periampullary tumors, particularly pancreatic ductal adenocarcinoma (PDAC). However, the evidence regarding safety and efficacy of LPD compared to open pancreatoduodenectomy (OPD) remains unclear. Methods: According to PRISMA guidelines, we searched PubMed, Embase, and Cochrane Library in December 2023 for randomized controlled trials (RCTs) that directly compare LPD versus OPD in patients with periampullary tumors. Outcomes were stratified as intraoperative outcomes, postoperative complications, in-hospital and short-term, and prespecified subanalysis was performed in patients with PDAC. All statistical analysis was performed using R software version 4.3.1 with a random-effects model. Results: Five RCTs yielding 1,018 patients with periampullary tumors were included, of whom 511 (50.2%) were randomized to LPD group. The total follow-up time was 90 days. LPD was associated with a longer operation time (MD 66.75; 95% CI 26.59 to 106.92; p = 0.001; I2= 87%; Figure 1A), lower intraoperative blood loss (MD -124.05; 95% CI -178.56 to -69.53; p < 0.001; I2= 86%; Figure 1B), and shorter length of stay (MD -1.37; 95% IC -2.31 to -0.43; p = 0.004; I2= 14%; Figure 1C) as compared to OPD. In terms of 90-day mortality rates and number of lymph nodes yield, no significant differences were found between both groups. Subgroup analysis for PDAC consistently aligned with the overall results and provided relatively lower heterogeneity compared to the primary analysis. Conclusions: Our meta-analysis of RCTs suggests that LPD is an effective and safe alternative for patients with periampullary tumors, with lower intraoperative blood loss and shorter length of stay.
A phase I/II study of enzalutamide in combination with indomethacin in men with castration-resistant prostate cancer (CRPC).
Authors: Leibrandt Ryan , Ullah Ayman Teeham , Verma Rashmi , Gao Allen , Lara Primo N. , Pan Chong-xian , Parikh Mamta
Published: July 2024

e17027

Background: Metastatic castration resistant prostate cancer (mCRPC) remains an incurable disease despite recent advances in therapy. In patients (pts) receiving the second-generation androgen receptor antagonist enzalutamide (enza), primary or adaptive resistance can occur due to upregulation of the steroidogenesis pathway, including aldo-keto reductase 1C3 (AKR1C3), which can also upregulate intratumoral androgen synthesis. Indomethacin, a non-steroidal anti-inflammatory drug and selective inhibitor of AKR1C3, demonstrates synergistic activity when combined with enza against enza-resistant CRPC in vitro and in vivo. We thus sought to study this combination in a clinical trial. Methods: This investigator-initiated Phase I/II trial enrolled pts with enza-naive mCRPC on androgen deprivation therapy. Prior abiraterone was allowed. Pts must have adequate organ function and ECOG performance status 0-2. In the phase I lead-in, a 3+3 dose de-escalation design was used to identify the recommended Phase II dose (RP2D) of indomethacin in combination with enza 160 mg oral (PO) once daily, after which a Phase II expansion proceeded. Pts continued treatment until disease progression or unacceptable toxicity. Co-primary endpoints were safety and PSA response, defined as 50% or more reduction from baseline. Secondary endpoints included overall response as determined by Prostate Cancer Working Group 2 criteria (PCWG2). Results: From 2017 - 2022, 26 pts were enrolled, with a median age of 71 (range 50-88), primarily white (n=16, 62%), median baseline PSA 19.45 (range 1.5-210), ECOG 1 (n=12, 46%), and most received prior abiraterone (n=24, 92%). In 6 pts enrolled to the phase I cohort, there were no grade 3 adverse events (AEs); RP2D of indomethacin was 50mg PO twice daily. All 26 pts were evaluable for safety and efficacy. Most common treatment-related AEs (n; %) were nausea (12; 46%), fatigue (11; 42%), diarrhea (8; 31%), hypertension (7; 27%), anorexia (6; 23%). Most common ≥ grade 3 treatment-related AEs were acute kidney injury (3; 12%), hypertension (3; 12%), and anemia (2; 8%). PSA response was observed in 8 pts (31%). By PCWG2, 14 pts (54%) experienced stable disease, while 10 pts (38%) had progressive disease. Conclusions: The combination of enza and indomethacin was safe, clinically feasible, and had clinical activity in pts with abiraterone-pretreated mCRPC. Further correlative studies are needed to identify pts who may benefit from AKR1C3 inhibition. Clinical trial information: NCT02935205 .
Clinical efficacy and safety analysis of immune checkpoint inhibitors combined with concurrent chemoradiotherapy for stage IIIC1-IVA cervical cancer: A prospective cohort study.
Authors: Ma YiMing , Zhang Mingchuan , Wu Hao , Chen Huimin , Wang Dandan , Xu Yuanyuan , Cheng Shuxia
Published: July 2024

e17505

Background: Stage IIIC1 with larger/more short lymph node diameters and IIIC2-IVA cervical cancer patients had a particularly poor prognosis. Clinical practices have found that stage IIIC1-IVA patients diagnosed with pelvic lymph node short diameter ≥ 1.5cm/number of positive lymph nodes ≥ 3, or paraaortic lymph node metastasis, had a higher recurrence rate and lower overall survival rate. The overall survival rate is approximately 29% -52%. Sequential systemic chemotherapy after concurrent chemoradiotherapy (CCRT) can not improve survival in such patients. However, the current research results on the combination of CCRT with immune checkpoint inhibitors for cervical cancer are not ideal, which may be due to the lack of stratified analysis. This study compared the efficacy and safety of CCRT and combined use of immune checkpoint inhibitors (non sequential) for stage IIIC1-IVA cervical cancer through the cohort analysis, and analyzed the prognostic factors. Methods: Patients diagnosed with stage IIIC1-IVA cervical cancer who underwent concurrent chemoradiotherapy from October 2019 to October 2022 were enrolled. Patients were divided into the study group (35 cases) receiving Sintilimab concurrently with chemoradiotherapy and the control group (35 cases) receiving standard treatment. The primary endpoints were the assessment of one-year progression-free survival (PFS), objective response rate (ORR), and associated influencing factors. Secondary endpoints included treatment-related adverse events (TRAEs). Results: The one-year PFS rates were 88.6% in the study group and 62.9% in the control group, showing a significant difference (χ2=6.293, P=0.012). The median PFS was not reached. The ORR for tumor response was 74.30% in the study group, significantly higher than the 51.43% in the control group (P=0.048). Univariate analysis identified tumor maximum diameter (p = 0.01) and concurrent use of ICIs (p = 0.039) as prognostic factors for PFS. Multivariate Cox analysis also revealed tumor maximum diameter (p = 0.0121) and concurrent use of ICIs (p=0.049) as independent predictors of PFS. The most common TRAEs in both groups included leukopenia, decreased appetite, nausea/vomiting, and fatigue, with no significant differences in incidence (P>0.050). Grade ≥3 TRAEs were most frequently leukopenia (47.5%) and thrombocytopenia (17.1%) in the study group and leukopenia (51.4%) in the control group. All adverse reactions were alleviated after symptomatic treatment, dose reduction, or discontinuation, and no TRAE-related deaths occurred. Conclusions: In patients with stage IIIC1-IVA cervical cancer undergoing definitive concurrent chemoradiotherapy, the addition of ICIs may improve patient survival with manageable safety.
Predictive value of C reactive protein (CRP) and D-dimer in patients with advanced cervical cancer treated with sintilimab and anlotinib.
Authors: Liu Jing , Chang Lele , Li Li , Zang Lele , Zhu Fei , Zhang Huiqi , Zhu Mingxuan , Xu Qin
Published: July 2024

e17525

Background: The Sintilimab plus Anlotinib in patients with advanced cervical cancer trial was a single-arm, phase II study that showed promising activity of the programmed death-1 (PD-1) inhibitor sintilimab plus the vascular endothelial growth factor receptor inhibitor Anlotinib in patients with advanced cervical cancer. We aimed to identify prognostic values of inflammation biomarkers and coagulation biomarkers in advanced cervical cancer treated with Sintilimab and Anlotinib. Methods: We conducted a post-hoc analysis of the data from the ALTER-C201 study (Clinical trial information: ChiCTR1900023015). The predictive value of coagulation variables and inflammation variables was evaluated by receiver operating characteristic (ROC) curves. Through Cox hazards regression models, prognostic factors were determined for overall survival (OS). Survival curves were visualized by Kaplan–Meier method and compared through Log-rank analysis. Results: We involved 41 patients and followed up for 38.0 (range, 0.6–44.0) months. According to the ROC curve, the predictive values of baseline CRP and D-dimer are better than other indicators, with area under the curve (AUC) values of 0.748 and 0.848, respectively. The cut-off values for D-dimer and CRP are 1.75ug/ml and 10.9mg/L, respectively. Through regression analysis, we demonstrated that CRP (HR 2.591; 95%CI 1.099–6.106; P = 0.030) and D-dimer (HR 2.669; 95%CI 1.154–6.173; P = 0.022) were independent prognostic factors. Compared to patients with CRP ≥ 10.9mg/L, those with CRP < 10.9mg/L have a longer OS (28.93 months, 95% CI, 15.23 to not reached v 10.57 months, 95% CI, 6.14 to not reached; log-rank test, P = 0.007). Compared to patients with D-dimer ≥ 1.75ug/ml, those with D-dimer < 1.75ug/ml have a longer OS (28.93 months, 95% CI, 17.09 to not reached v 10.73 months, 95% CI, 4.63 to not reached; log-rank test, P = 0.005). Conclusions: CRP and D-dimer predict survival in advanced cervical cancer patients undergoing combined ICI/ VEGF-TKI therapy. We advocate further work to validate utilisation of CRP and D-dimer as prognostic biomarkers for advanced cervical cancer in clinical practice.
Survival in patients with cervical cancer undergoing chemo-radiotherapy in a middle-income country.
Authors: Argüello Mario , Pulla Fausto Emiliano , Morquecho Walter , Reyes José Luís , Campoverde Felipe , Engracia Ruth , Tamayo Patricia Rocío , Paulson Guillermo , Santacruz Mayra
Published: July 2024

e17527

Background: Cervical cancer (CC), being a high-incidence pathology in Ecuador, requires a priority multidisciplinary therapeutic approach to obtain an optimal benefit in overall survival. The objective of the present study is to describe overall survival (OS) in patients with locally advanced CC treated with chemoradiation according to histological type and clinical stage. Methods: It is an observational, analytical, retrospective, longitudinal study of patients with stage IIB-IVA CHD who received treatment with chemoradiation from January 2010 to December 2014 with a 10-year follow-up. The SPSSv29 statistical system was used. Survival analysis was performed using the Kaplan-Meier method and the Log-Rank test. Results: Of 1909 patients, 1581 were excluded because they did not meet eligibility criteria. 328 received chemoradiation. The overall survival result was 43%. According to histological type, 276 patients presented squamous cell carcinoma (SCC) and 52 adenocarcinoma (AC), presenting a survival of 44% for SCC and 35% for AC. The calculation by clinical stage, II-B shows a survival of 46%. For stage IV-A 20% up to 46 months. The Log-Rank test (p=0.04) shows a significant statistical value. Conclusions: The 10-year overall survival was 43%, showing an essential difference for the histological type, being higher for squamous cell carcinoma, and also showing a significant difference between the stages. [Table: see text]
Clinical phosphoproteomics reveals aberrant signalling pathways and kinases in treatment-resistant cervical cancer.
Authors: Kumar Prashant , Chauhan Richa , George Irene A. , Sambath Janani , Dhawale Ekta R. , Singh Manisha , Trivedi Vinita , Venkataramanan R.
Published: July 2024

e17529

Background: Cisplatin-based concurrent chemoradiation therapy (CCRT) is the standard for locally advanced cervical cancer. While cisplatin stands out as a highly effective chemotherapeutic option for cervical cancer, resistance to the drug often triggers relapses. Moreover, previous studies have highlighted the detrimental impact of cisplatin's toxicity, which extends beyond treatment efficacy to influence the overall prognosis of patients. Combination treatment with drugs targeting different molecular pathways increases the effectiveness of the treatment by disrupting multiple critical processes that cancer cells rely on for survival. Herein, we analyzed the phosphoproteomic profile of cervical cancer patients resistant to concurrent chemoradiotherapy to identify the crucial kinases responsible for therapeutic resistance. Methods: We used mass spectrometry for phosphoproteomic analysis to study signaling pathways and dysregulated kinases in CCRT resistance. Biopsy samples collected pre-therapy were processed by protein extraction, digestion, and labeling with 10-plex TMT. Peptides were fractionated by basic pH liquid chromatography, enriched using IMAC, and analyzed on an Orbitrap-Fusion-Tribrid mass spectrometer. Data analysis was performed using Proteome Discoverer and various bioinformatics and statistical methods. Results: The phosphoproteomic analysis revealed distinct phosphorylation signatures between the responders and non-responders. In concordance with the phosphoproteomic data the expression of phospho-SMC1A and CSNK2A1 is preserved in non-responder cohort of cervical cancer patients in concordance with the phosphoproteomic data. Further, the pathway analysis showed elevated presence of the DNA repair pathway in the treatment-resistant cohort. Furthermore, dysregulation in the phosphorylation of key DNA repair proteins, such as SMC1A, HMGN1, MGMT, DDB2, and MSH6, suggests their involvement in treatment. The kinase prediction analysis suggested the activation of kinases such as CSNK2A1, PRKDC, PLK1, NEK2 and ATM in non-responders. Subsequently, cell line based functional experiments indicated the potential of CSNK2A1 inhibitor silmitasertib in sensitizing the cells to cisplatin treatment. Conclusions: Phosphoproteomicanalysis of the cervical cancer revealed distinct phosphorylation signature and kinases involved in treatment resistance. Our findings indicated that dysregulated phosphorylation and increased expression of the kinase CSNK2A1 play a pivotal role in the treatment response of cervical cancer patients. Moreover, CSNK2A1 can sensitizes the cells to cisplatin uncovering the potential of combination treatment strategies. Our study uncovers the potential of clinical phosphoproteomics to design tailored treatment strategies in patients resistant to standard treatments.
Liquid biopsy detection of structural variant breakpoints to monitor ovarian cancer clonal evolution.
Authors: Li Jian , Takamatsu Shiro , Little Latasha , Celestino Joseph , Lawson Barrett , Hillman Robert Tyler
Published: July 2024

e17538

Background: Chemotherapy is effective at inducing remission for most patients with high grade serous ovarian cancer (HGSOC), yet relapse is frequent. Methods to interrogate the clonal composition and molecular properties of minimal residual disease are needed to better understand the mechanisms of HGSOC relapse. To address this unmet need, we developed and validated a novel cfDNA-based approach for tracking on-treatment clonal evolution using tumor-informed structural variants (SVs). Methods: Genomic DNA (gDNA) was isolated from cryopreserve multisite pre-treatment HGSOC biopsies and matched germline samples and whole genome sequencing (WGS) was performed. cfDNA was isolated from contemporary pre-treatment plasma. High confidence SVs were identified from multisite WGS using a consensus method incorporating five published SV calling algorithms. Tumor-informed bespoke quantitative PCR primer/probe sets were designed to interrogate SVs breakpoints in tumor gDNA and matched cfDNA. Results: Optimization of the methodology was first performed using synthetic cfDNA generated by ultrasonication of DNA from ovarian cancer cell lines. WGS was used to identify SVs and SV breakpoint-spanning PCR assay exhibited 90% sensitivity and 89% specificity in detection of WGS-informed SVs. 11 validated SVs breakpoint-spanning PCR assays had specific amplifications in synthetic cfDNA. 8 SVs breakpoint-spanning quantitative PCR primer/probe sets were synthesized for qPCR (real-time PCR) and ddPCR (digital droplet), the custom TaqMan probe assays had significant increased sensitivity and superior specificity. When cutoff value of negative was set to “undetected” in qPCR and 0 copies/ul in ddPCR, the sensitivity and specificity of custom TaqMan probe assays can still be 100%. . After screening 18 SVs by tumor-informed SV breakpoint-spanning PCR assays, 8 SVs custom TaqMan probe qPCR assays demonstrated 100 % sensitivity and specificity in multisite biopsy samples. 3 shared and 3 private SVs custom TaqMan probe ddPCR assays were selected for absolute quantification, none of these assays had false positive or false negative when 0 copies/ul was used for cutoff value. 1 shared SV custom TaqMan probe ddPCR assay measured 0.947 copies/ul in cfDNA and 0 copies/ul in matched germline control. Altogether, our multi-layer screening approach yields the “perfect”- high sensitivity and specificity- SV breakpoint-spanning assays that are ready to apply for SVs detection in cfDNA. Conclusions: Detection of SVs from pre-treatment cfDNA using tumor-informed breakpoint-spanning ddPCR is feasible and may enable a novel and sensitive method for monitoring on-treatment disease burden. Work is ongoing to extend this method to private SVs with a goal of tracking treatment-induced tumor clonal dynamics using cfDNA.
Identification of tumor-marker gangliosides for early cancer detection: A multi-platform approach.
Authors: Blackler Adele , Culp-Hill Rachel , Law Robert A , Radnaa Enkhtuya , Tyler Abby , Halstead Susan , Willison Hugh
Published: July 2024

e17551

Background: Tumor-marker gangliosides (TMGs) have enormous potential for early-stage cancer detection as diagnostic biomarkers despite being relatively understudied in this context. AOA Dx is focused on the analytical development of three separate platforms for the quantitation of TMGs in human serum. The development of these platforms for TMG quantitation may allow for the identification of diagnostic signatures for early-stage cancer detection. Methods: First, we are developing a pipeline of antibody-based assays to target TMGs. To aid in development of multiple immunoassays, we collected specificity and affinity data on commercial and proprietary antibodies targeting TMGs using glycoarrays. We are also currently using two immune-based platforms to target TMGs. We have developed an enzyme-linked immunosorbent assay (ELISA) and we have implemented high-performance thin-layer chromatography (HPTLC) to detect individual and total gangliosides. Additionally, we are applying both targeted and untargeted mass spectrometry to human serum from confirmed cancer diagnoses. Results: The specificity and affinity data from the glycoarrays confirm that our TMG antibodies have negligible cross-reactivity and are suitable for diagnostic platform development. Additionally, our developed ELISA allows for the quantification of TMGs in diverse and complex matrices including human serum and plasma, cell lines, and exosomes. HPTLC also detects individual and total gangliosides in each of these matrices, which allows for high-throughput analysis for TMG quantitation. Finally, the application of both targeted and untargeted mass spectrometry has identified multiple TMGs characterized by unique lipid tails. Notably, MS analysis shows that the serum of melanoma and ovarian cancer patients exhibited significantly increased levels of several ganglioside species compared to age-matched healthy serum, further highlighting the potential of TMGs as a promising avenue for cancer diagnosis. Further experiments will focus on refining all platforms. We will also expand the demographic representation of our human serum sample cohort to confirm the initial findings from our mass spectrometry experiments and continue to use this platform to identify additional TMGs of interest. Conclusions: AOA Dx is advancing the development of a multi-platform approach for the detection of TMGs. Our objective is the identification of a diagnostic disease signature for early-stage cancer detection. The validation of this type of diagnostic panel would allow for expedited diagnosis and treatment of cancers currently diagnosed at late stages, ultimately reducing healthcare costs and increasing survival rates. Future research will aim to validate these biomarkers in independent prospective studies.
Prevention of pemetrexed-induced rash with low-dose dexamethasone in patients with NSCLC receiving immunotherapy: A prospective, single-arm clinical trial.
Authors: Zhang Jing , Zhou Xue , Jia Yuming , Huang Shenglan , Wang Qiu , Jiang Mao-Qiong , Li Ting , Jiang Jian , Liqiang Zhong , Ye Xujuan , Lei Kaijian
Published: July 2024

e20596

Background: Pemetrexed is highly active in non-small cell lung cancer (NSCLC). Rashes associated with pemetrexed are more commonly than other chemotherapies. It is recommended that patients receive pemetrexed are required dexamethasone as a pretreatment. However, the immunosuppressive effects of dexamethasone especially high doses of glucocorticoids may reduce the efficacy of immune checkpoint inhibitors (ICIs). This study aims to prospectively evaluate the efficacy of low-dose dexamethasone in pretreatment of pemetrexed-induced rash, particularly in NSCLC patients receiving immunotherapy. Methods: This is a prospective, single-arm clinical trial that enrolled NSCLC patients scheduled to receive chemotherapy including pemetrexed, with/without immunotherapy. Patients received low-dose dexamethasone: 8mg, 4mg, 2 mg of dexamethasone for 3 days recpectively from the day preceding pemetrexed (the recommended administration is 8 mg/day of dexamethasone for 3 days) . Rash severity is described according to CTCAE v5.0 (Common toxicity criteria for adverse events version 5.0). The primary endpoint was the 3-week incidence of rash after pemetrexed. Results: A total of forty-seven stage IIB-IVB patients were enrolled between February 2022 and December 2023, including eighteen patients were combined with immunotherapy. They all received the low-dose dexamethasone regimen prior to a total of 149 cycles of chemotherapy. The incidence of skin rash after 3 weeks was of 7 episodes in 149 cycles (4.70%), 7 patients (12.77%) presented rash. In the eighteen patients receiving immunotherapy, rash within 3 weeks after pemetrexed administration occurred in 4 episodes in 72 cycles (5.56%), 4 patients ( 22.22%) presented rash. And one patient presented two episodes of cutaneous toxicity. Most skin rash episodes were of grade 1 (approximately 85%), while the rest were grade 2 (approximately 15%). No grade 3 or 4 skin rash was reported in the entire study population. Most cutaneous toxicities occurred during the first or second cycle. The incidence of rash in this study was significantly lower than the rate of 67.5-93% reported in patients treated without corticosteroids and did not increase compared with the rate of 14-56% reported in patients treated with corticosteroids. Conclusions: Administration of low-dose dexamethasone (8mg, 4mg, 2 mg of dexamethasone for 3 days from the day preceding pemetrexed) significantly reduces the incidence of rash after pemetrexed. The regimen may provide a standard preventive strategy for pemetrexed-induced rash, especially in NSCLC patients combined with immunotherapy(This study is registered with the Chinese Clinical Trial Registry (ChiCTR2400079622). Clinical trial information: ChiCTR2400079622.