bluuebunny/crossref_metadata_2025 huggingface dataset:
The efficacy of atezolizumab plus bevacizumab in the treatment of unresectable hepatocellular carcinoma in cirrhotic and non-cirrhotic patients.
Authors: Aranda-Gutierrez Alejandro , Conde-Flores Emilio , Meraz-Brenez Andres , Escorza Salvador , Meneses-Medina Mónica I. Isabel , Huitzil-Melendez Fidel David , de la Mora-Molina Héctor , Rosas Camargo Vanessa
Published: July 2024

e16214

Background: The IMbrave150 trial established that the combination of atezolizumab plus bevacizumab (AB) confers a significant progression-free survival (PFS) benefit when compared with sorafenib in patients with unresectable hepatocellular carcinoma (HCC). However, the nuanced impact of cirrhotic status on treatment response was not established by the study, leaving a critical aspect of patient stratification and outcomes yet to be fully understood. Methods: We conducted a retrospective single-center study of patients with HCC treated with AB between 2020 and 2023. Eligible patients were those who underwent at least one cycle of AB and had a follow-up period of at least three months post-AB initiation. Independent samples T-test and X2 and Fisher’s exact tests were used to evaluate associations between variables. PFS was calculated using the Kaplan-Meier method and compared according to cirrhotic status using the log-rank test. A Cox regression analysis was performed to estimate survival hazard ratios (HR). Results: Among 28 patients, the mean age at diagnosis was 64 years (SD 11), 18 (64%) were male, 26 (93%) had Child-Pugh (CP) class A liver function, and 18 (64%) were cirrhotic. Most patients presented with Barcelona Clinic Liver Cancer stage C disease (61%) and received AB in the first-line setting (93%). Clinicopathological features according to cirrhotic status are detailed in Table 1. With a median follow-up of 14 months (95% CI 8-20) since AB initiation, 16 progression events were recorded, resulting in a median PFS of 12 months (95%CI 6-18) for the entire cohort. Univariate analysis revealed an inferior median PFS in patients with cirrhotic HCC (7 months [95%CI 5-9] vs. not reached [p = 0.038]). However, in a multivariate Cox analysis, only obesity emerged as a significant predictor of an inferior PFS (HR 4.6; 95% CI 1.3 - 16.0, p = 0.018). Conclusions: In our study, cirrhosis was not associated with an inferior PFS. Notably, the majority of cirrhotic patients in this cohort exhibited CP A liver function, so uncertainties persist regarding the impact of cirrhosis on cancer progression in patients with CP B and C liver function. Further investigation is warranted to comprehensively evaluate whether cirrhotic, non-cirrhotic, and obese subgroups respond differently to AB therapy. [Table: see text]
Nivolumab monotherapy and associations in the treatment of advanced unresectable biliary tract cancer (BTC): A systematic review and meta-analysis.
Authors: Filogonio Victor , Maia Yara Rafaela , Maia Lucas Henrique , Beck Mauren Carbonar , Beck Theodoro
Published: July 2024

e16216

Background: Patients with advanced unresectable BTC have a poor prognosis, and treatment options are limited and with variable response rates. Nivolumab (NIVO), a PD-1 inhibitor, has shown its effectiveness against multiple cancer types and has been tested as a therapeutic option in diverse settings and associations. Methods: We performed a systematic review and single arm meta-analysis of clinical trials of NIVO monotherapy or combined therapy in advanced unresectable BTC. PubMed, Embase, and Cochrane database were searched for clinical trials published up to May 1, 2023. Data were extracted from published reports and quality assessment was performed per Cochrane recommendations. The primary endpoints of interest were objective response rate (ORR = CR+PR) and disease control (DC = SD or better response) per RECIST v1.1, at any period of the trial. Results: Out of 80 database results, 6 clinical trials and 358 patients were included, all were using some form of NIVO therapy. Overall, NIVO and associations present an ORR = 13% (95% CI 0.08-0.16, I² = 23%, p = 0.26) and DC = 39% (95% CI 0.27-0.51, I² = 69%, p < 0.05). NIVO monotherapy present an ORR = 6% (95% CI 0.02-0.10, I² = 36%, p = 0.19) and DC = 28% (95% CI 0.04-0.51, I² = 87%, p < 0.001) while NIVO + ipilimumab association show an ORR = 11% (95% CI 0.004-0.22, I² = 76%, p < 0.05) and DC = 37% (95% CI 0.24-0.49, I² = 28%, p = 0.23). NIVO + gencitabine + cisplatin association trials reported an ORR within 13-18% and DC around 32%. This data suggests that associations of NIVO present higher efficacy in the treatment of BTC and should be considered among the first choices of therapy, however drug adverse effects tolerability might play an important part in the individualized patient care. Conclusions: There are marked limitations to the applicability of these findings in clinical practice, therefore a cautionary approach to this data is recommended, given their overall low statistical power, heterogenous study design, and tolerability to adverse effects. New trials of NIVO + associations with better standardized outcomes and comparative arms for different associations and populations will help to better clarify the effects of NIVO in the treatment of advanced unresectable BTC. [Table: see text]
Clinicopathologic and treatment characteristics of mixed hepatocellular carcinoma-intrahepatic cholangiocarcinoma (HCC-ICC).
Authors: Ozer Muhammet , Goksu Suleyman Yasin , Sahin Ilyas
Published: July 2024

e16218

Background: Mixed hepatocellular carcinoma-intrahepatic cholangiocarcinoma (HCC-ICC) represents a rare subtype of primary hepatic malignancy demonstrating morphological and biological features characteristic of both Hepatocellular Carcinoma (HCC) and Intrahepatic Cholangiocarcinoma (ICC). In this study, we describe the clinical and tumor characteristics of survival in HCC-ICC by using a large cohort. Methods: We selected patients diagnosed with HCC‐ICC, HCC, or ICC between 2011 and 2018 and were identified from the National Cancer Data Base (NCDB) using the International Classification of Diseases for Oncology codes. Baseline characteristics were delineated using percentages. Median overall survival (OS) was calculated using the Kaplan-Meier method. Demographic variables (age at diagnosis, gender, race, insurance status), comorbidity score, and treatment features were included. Short‐ and long‐term outcomes were evaluated through univariate analysis. Results: Out of 124,723 patients, 84.6% were diagnosed with HCC, 14.5% with ICC, and 1% with HCC‐ICC. Median survival was significantly better in HCC compared to HCC-ICC and ICC patients (16.2 months, 10.8 months, and 9.4 months, respectively, p < 0.001). Surgical intervention was used by 26.3% of HCC-ICC cases, 19.2% of ICC cases, and 9% of HCC cases. Multiagent chemotherapy was notably more utilized in ICC compared to HCC-ICC and HCC (42.6%, 22.8%, and 5.4%, respectively, p < 0.001). Meanwhile, single-agent chemotherapy was more commonly administered in HCC than in HCC-ICC and ICC (32.3%, 16.5%, and 11.4%, respectively, p < 0.001). Conclusions: HCC-ICC is an aggressive primary liver malignancy with a worse prognosis than HCC and ICC. The primary treatment approach for operable cases continues to be major hepatectomy combined with resection of hilar lymph nodes. Further research is urgently needed to better understand the exact role of the systemic therapies in managing HCC-ICC.
Short-term and long-term outcomes of transduodenal ampullectomy for patients with early ampullary cancer.
Authors: Miyamoto Ryoichi
Published: July 2024

e16244

Background: Transduodenal ampullectomy (TDA) has been attempted in early ampullary cancer. However, the indication and extent of TDA with curative intent remain controversial. Here, we address the perioperative and long-term outcomes of patients with early ampullary cancer who underwent TDA. Methods: Ten early ampullary cancer patients who underwent TDA and 11 early ampullary cancer patients who underwent subtotal stomach-preserving pancreatoduodenectomy (SSPPD) at this institute were respectively enrolled. Among this cohort, we analyzed the perioperative outcomes and long-term outcomes. Results: In terms of the perioperative outcomes between the TDA and SSPPD groups, the TDA group exhibited a shorter operating time (244 minutes vs. 390 minutes, p = 0.003), less intraoperative blood loss (67.5 grams vs. 774 grams, p = 0.006) and shorter length of postoperative hospital stay (15 days vs. 33 days). With respect to the postoperative nutrition status, the TDA group exhibited less postoperative weight loss (0.67% vs. 8.95%, p = 0.021), a better CONUT score (1.0 vs. 2.1, p = 0.011) and a better PNI score (42.9 vs. 40.9, p = 0.018). The 5-year survival rate in the adenoma with high-grade dysplasia (HGD) and T1a (M) groups was 100%, while the median survival time in the T1a (OD) group was 20.7 months (p = 0.0028). Conclusions: TDA is assumed to be a feasible and effective surgical procedure for the treatment of selected patients with early ampullary cancer, including patients with adenoma with HGD or T1a (M) ampullary cancer.
Peritumoral HLJ1-STAT3 pathway investigation in carcinogen-induced hepatocellular carcinoma.
Authors: Luo Wei-Jia , Chien Min-Hui , Yu Sung-Liang , Yang Pan-Chyr , Su Kang-Yi
Published: July 2024

e16251

Background: Hepatocellular carcinoma (HCC) is a major global health issue and its treatment options have been limited. Therefore, it is urgent to develop cancer biomarkers for defining cancer risk, diagnosis, prognosis, and even finding new therapeutic targets. Human Liver DnaJ-Like Protein (HLJ1), which belongs to DnaJ heat shock protein family (HSP40) member B4 (DNAJB4), has been identified as a tumor suppressor in various cancers including lung cancer and colorectal cancer. Though the biological function of HLJ1 in either cancer or the liver has emerged in recent years, the precise role of HLJ1 in HCC carcinogenesis is still unclear. Methods: Samples for gene expression cDNA microarray were from 6-8 weeks wild-type (WT) and HLJ1 knockout (HLJ1-/-) mice liver. For the long-term carcinogenesis study, both mice are injected with 20 mg/kgbw diethylnitrosamine (DEN) at postnatal day 15. After that, 50 mg/kgbw DEN was administrated weekly to mice between the ages of 4 to 12 weeks. Mice were sacrificed at ages 30 and 36 weeks to assess the tumor count and size. For the short-term DEN study, 6-8-week-old mice were injected with 100 mg/kg DEN, and 24 and 48 hours after administration the liver tissues were frozen and fixed for western blotting and IHC analysis. Cancer cell transplantation was performed by intrasplenic injection of HLJ1-wildtype LLC and B16F1 cells into both genotypes. Clinical information of 362 liver cancer patients from the TCGA database was analyzed for the correlation between HLJ1 expression and survival. Results: In cDNA microarray analysis, We demonstrated that HLJ1 deficiency led to HCC gene signatures associated with activated IL-6/STAT3 signaling pathways. We used the DEN as a carcinogen and found STAT3 and H2AX phosphorylation induced by short-term DEN treatment was amplified in HLJ1-deficient mice. In long-term DEN experiments, HLJ1 deletion promoted tumor initiation and proliferation at the early and late stages of HCC progression accompanied by pronounced STAT3 phosphorylation in the normal part instead of the tumor part. Furthermore, transplantation of HLJ1-wildtype B16F1 and LLC cell lines into HLJ1-deficient mice led to more tumorigenic phenotype than into wildtype mice. Clinical information of 362 liver cancer patients from the TCGA database exhibited that higher expression of HLJ1 in the tumor part is correlated to a lower disease-specific survival rate. Conclusions: In summary, HLJ1 protects against DEN-induced HCC hepatocarcinogenesis through the regulation of STAT3 signaling in the peritumoral normal cells. Hence, HLJ1 can be a prognostic biomarker for liver cancer and a promising therapeutic target for HCC in the future.
Surgical resection versus thermal ablation: Comparison of sequential options after successful TACE downstaging therapy for unresectable hepatocellular carcinoma—A long-term multi-institutional study.
Authors: An Chao , Wu Pei-Hong , Huang Jin-Hua
Published: July 2024

e16258

Background: Transarterial chemoembolization (TACE) is an effective and safe treatment for unresectable hepatocellular carcinoma (uHCC). However, the selection of sequential therapeutic modalities after TACE downstaging therapy is still controversial. The aim of this study is to compare the efficacy and safety of surgical resection (SR) and thermal ablation (TA) after successful TACE downstaging therapy for uHCC. Methods: In this real-world multi-institutional study from June 2008 to October 2022, 8,219 consecutive patients with HCC underwent conventional TACE at 12 hospitals. Patients underwent successful TACE downstaging therapy for uHCC beyond Milan criteria, who were assigned into SR group and TA group. The propensity score matching (PSM) was applied to reduce selection bias between groups. Cumulative overall survival (OS) and progression-free survival (PFS) were compared using the Kaplan‒Meier method with the log-rank test. A comparison analysis of major complications was performed using the c2 test. Results: 609 (7.4%) patients received SR or TA after TACE. After PSM 1:1, 185 patients in the SR group were matched with 185 in the TA group. After 4.5 years of median follow-up time, the cumulative 1-, 3-, 5- and 10-year OS rates were 98.8%, 89.3%, 82.9% and 64.4% in the SR group and 99.5%, 88.4%, 75.3% and 53.9% in the TA group, respectively, showing no significant difference ( P = .381). The cumulative 1-, 3-, 5- and 10-year PFS rates were 88.5%, 69.2%, 58.8% and 32.2% in the SR group and 90.6%, 71.4%, 53.1% and 32.0% in the TA group, respectively, showing no significant difference ( P = .855). The incidences of major complications were 6.5% in the SR group and 7.6% in the TA group, showing no significant difference ( P = .684). Conclusions: For uHCC patients beyond the Milan criteria received TACE downstaging therapy, TA might be acceptable as an alternative to SR in first-line sequential treatment scheme.
Second-line (2L) treatment patterns and clinical outcomes among real-world (RW) patients (pts) with metastatic pancreatic ductal adenocarcinoma (mPDAC) treated with FOLFIRINOX (FFX) or gemcitabine + nab-paclitaxel (GnP) in the first-line (1L).
Authors: Paluri Ravi Kumar , Silver Michelle , Cockrum Paul , Dennen Syvart
Published: July 2024

e16322

Background: FFX and GnP are the most common 1L treatments for pts with mPDAC. Approximately half of pts treated with these regimens continue to 2L, though optimal 2L treatment is unclear. We identified a RW sample of mPDAC pts treated with 1L FFX or GnP and assessed their 2L treatment patterns, duration of therapy (DoT), overall survival (OS), and time to next treatment (TTNT). Methods: This retrospective observational study utilized the Ontada Clinical Data View: Pancreatic Cancer database. Adult pts diagnosed with mPDAC between November 2018 and November 2021 who initiated 1L treatment with FFX or GnP ≤90 days from metastatic diagnosis date were included. To observe 2L treatment patterns, pts were required to have ≥1 year of follow-up unless death occurred first. Pts were censored at date of last activity absent death. Kaplan-Meier analyses were used to assess the median OS and TTNT from the start of 1L. Pts were grouped into five treatment categories: 1L FFX-only, 1L FFX + 2L GnP, 1L FFX + 2L other, 1L GnP-only, and 1L GnP + any 2L. Pts with 2L treatments were not restricted by whether they received 3L therapy or later. Results: 936 1L GnP and 712 1L FFX pts met the study inclusion criteria. 572 (61%) 1L GnP pts received 1L GnP-only and 364 (39%) received 1L GnP + any 2L (“any 2L” included 78 Nal-IRI, 59 FOLFOX, 57 FFX pts, and 170 pts with various combinations of chemotherapies and/or targeted therapies, with < 50 pts per regimen). 300 (42%) 1L FFX pts received 1L FFX-only, 287 (40%) received 1L FFX + 2L GnP, and 125 (18%) received 1L FFX + 2L other (“2L other” included 35 capecitabine monotherapy pts, 27 G monotherapy pts, all other regimens < 20 pts). Pts with 1L FFX were younger, slightly more likely to be male, and had slightly better ECOG scores than 1L GnP pts. Median 1L DoT was shorter for 1L-only pts compared to pts with 2L therapies. Median OS was shortest for 1L-only pts and longest for 1L FFX + 2L other. Median OS was similar for 1L FFX + 2L GnP and 1L GnP + any 2L. Median TTNT was similar across treatment categories with a 2L. Conclusions: In a RW sample of mPDAC pts, those with 1L-only had poor survival. Pts with 1L FFX + 2L GnP had a similar survival to 1L GnP + any 2L. [Table: see text]
Interaction of BRCA1 vs BRCA2 pathogenic variants with primary tumor location in pancreatic cancer.
Authors: Hood Ryan , Seewald Nicholas J. , Rathore Srishti , Reiss Kim Anna
Published: July 2024

e16326

Background: BRCA1/2 germline or somatic pathogenic variants (PVs) are found in 5-10% of pancreatic adenocarcinoma (PDAC) patients. Recent data suggest that BRCA2 PVs may be associated with increased overall survival (OS) compared to BRCA1 PVs after adjusting for treatment and clinical characteristics. Additionally, pancreatic tail PDAC was found to harbor PVs in BRCA1/2 more frequently compared to PDAC within the pancreatic head (HOP). We hypothesized that tumor location in patients with BRCA1 and BRCA2 PVs would associate with overall survival and somatic mutation profile. Methods: We conducted a retrospective cohort study using a database of patients with PDAC and BRCA1/2 PVs at an academic center. Demographic and clinical data were compared by Fisher’s exact test. OS was measured using date of death or last follow-up and compared by Cox proportional hazards regression adjusting for treatment with platinum-based chemotherapy and curative-intent surgical resection. Cases with available next generation somatic sequencing were reviewed. Results: There were no significant differences in age, sex, stage at diagnosis, ECOG status at diagnosis, tumor location, treatments, or sites of metastasis between patients with BRCA1 vs BRCA2 PVs. In the overall cohort, we observed no significant difference in OS between patients with BRCA1 vs BRCA2 (17.0 vs 20.2 months). However, survival analysis stratified by tumor location demonstrated that BRCA1 patients with HOP tumors had significantly worse OS compared to BRCA2 patients with HOP tumors (13.1 vs 25.7 months, p = 0.014) and had a significantly higher rate of TP53 mutations (100% vs 50%, p = 0.032). No significant differences in OS or rates of TP53 mutations were observed in the body/tail of the pancreas. Conclusions: These results suggest that there may be differences in rates of somatic variants between BRCA1- and BRCA2-related HOP PDAC and suggest an interaction between BRCA1/2 tumor biology and anatomical location. [Table: see text]
Nab-paclitaxel and gemcitabine (modified) in combination with oral cobimetinib and encorafenib following FOLFIRINOX in patients with metastatic G12D and G12V pancreatic cancer.
Authors: Ardalan Bach , Azqueta Jose Ignacio , England Jonathan , Sleeman Danny , Gonzalez Rosali
Published: July 2024

e16330

Background: Pancreatic cancer is the only human cancer in which most of the tumors are KRAS mutated. A majority of the mutations occur in codon 12. Mutations percentages are as follows: G12D (50%), G12V (35%) and G12R(12%). We are reporting on a pilot study in patients with advanced pancreatic cancer who have failed, or have become resistant to FOLFIRINOX. Thereafter the patients were placed on Nab-paclitaxel and Gemcitabine in combination with oral Cobimetinib and encorafenib. Methods: Patients with advanced pancreatic cancers are typically offered modified FOLFIRINOX followed by Nab-paclitaxel and Gemcitabine. After obtaining a written informed consent, we conducted a single arm study of patients with pathologic proven unresectable metastatic pancreatic cancer. Patients who had failed FOLFRINOX were placed on a modified regimen of Gemcitabine (1000mg/m2) and Nab-paclitaxel (125 mg/M2) on days 1 and 15 every 28-day cycle. Oral medications, Cobimetinib 20 mg bid and encorafenib of 150 mg bid were given. The oral chemotherapies were administered weekdays only during the 28-day cycle. The primary end point was to determine the response rate from the time the patients were placed on Nab-paclitaxel and Gemcitabine and the oral medication. The secondary endpoint was to assess the overall survivorship from the beginning of the therapy, and overall toxicities of the combination therapy. Twelve patients with advanced metastatic pancreatic cancer were enrolled on this pilot study. Six patients were male, and the median age was 67 years. Liver metastases were present in eight patients. Treatment was continued as long as there was no disease progression. CBC, CMP, CA19-9 was performed every other week. CT and PET scan was ordered every eight weeks. Results: Overall follow up is from 5 to 19 months (median 14 months). Segmental median survival from the start of oral therapy in conjunction with Nab-paclitaxel and Gemcitabine is 5 months (2-9 months). As from now,all patients are alive and 10 of 12 patients are on therapy. One patient who achieved pathologic response in the liver was deemed operable, and pathologically the distal pancreatectomy demonstrated NO disease. The other patient has progressed and is not on treatment. Grade 3 non-hematological toxicities included nausea, vomiting and fatigue in 3 of 12 patients. Hematological toxicities included neutropenia and neutrophil support was needed in 6 out of 12 patients. Median survivorship has NOT been reached. In this small study, we have observed a rapid and dramatic reduction in tumor volume. Conclusions: The combination of MEK and BRAF inhibitors with chemotherapy may be potentially active in pancreatic tumors (G12D and G12V). Based on the data presented, Nab-paclitaxel and Gemcitabine in combination with oral Cobimetinib and encorafenib needs to be further explored in a larger cohort of patients.
TisCRT-LAPC: A phase II study of tislelizumab combined with nab-paclitaxel and gemcitabine (AG) followed by consolidative radiotherapy in locally advanced pancreatic cancer (LAPC).
Authors: Guo Xi , Zhou Yuhong , Ji Yuan , Lou Wenhui , Wu Lili , Wang Wenquan
Published: July 2024

e16350

Background: We have previously reported that consolidative chemoradiotherapy following induced chemotherapy is an optimal regimen for LAPC. This study aimed to evaluate the clinical benefit of tislelizumab (anti-PD-1) plus AG chemotherapy sequenced by consolidative radiotherapy for therapy-naive LAPC. Methods: Patients (pts) with LAPC were enrolled and received tislelizumab (TIS) 200mg Q3W, nab-paclitaxel 125 mg/m2 and gemcitabine 1,000 mg/m2 on days 1 and 8 every three weeks for 6 cycles. Those who did not progressed continued to receive radiotherapy and tislelizumab. After that, tislelizumab and gemcitabine were ongoing until progression. The primary endpoint was 12-month progression-free survival rate, and secondary endpoints included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), safety and biomarker explore. Results: From April 2021 to December 2023, 30 pts were enrolled, 29 pts completed at least one efficacy assessment, 1 dropped out due to jaundice on liver damage for more than 6 weeks without medication. 17 males and 13 females with a median age of 58.5 years. 12.5% (3/24) progressed after TIS+AG treatment and did not receive radiotherapy, 87.5% (21/24) had completed radiotherapy and 5 pts were still receiving TIS+AG treatment. ORR was 31.0%, and DCR was 96.6%, respectively. The median follow-up time was 14.0 months, and the median PFS was 11.2 months (95%CI,7.6-26.6). The median OS was not reached. 6-month and 12-month PFS rates were 84.2% and 44.3%, respectively. Most patients (27/30) showed serum CA19-9 decline with different degrees.The most common treatment-emergent adverse events (TEAEs) were myelosuppression, rash, and fatigue. Grade 3/4 TEAEs were neutropenia in 5 patients, anemia in 1 patient, and rash in 1 patient. Immune-related AEs included 1 Grade-1 myocarditis, 1 Grade-1 pneumonia and 1 Grade-3 disfunction of liver. Conclusions: This study demonstrates the effectiveness and manageable safety of tislelizumab combined with AG chemotherapy sequenced by radiotherapy for LAPC. Exploratory analysis of correlative biomarkers suggests that KRAS ctDNA negative at baseline may be a pedictive markers benefit with treatments. Clinical trial information: ChiCTR2000040872.
Impact of personalized peptide neoantigen vaccines on immunologic responses in patients with pancreatic cancer.
Authors: Hu Landian , Zhang Yuchao , Kong Xiangyin , Wu Zhenchuan , Wang Hailong
Published: July 2024

e16351

Background: Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer that often resists conventional therapies. One of the most promising alternative treatments is personalized neoantigen vaccines that target specific mutations in each patient’s tumor. These vaccines aim to activate the immune system to fight cancer cells. However, how this type of vaccine affects immune cells across different vaccination phases is poorly understood. Methods: Here we report the safety and dynamic immunological responses of peptide-based vaccines after chemotherapy in patients with resected PDAC in a single-center open-label phase 1b trial (registered at ClinicalTrials.gov [NCT03558945]). The primary endpoint was safety, assessed by the incidence of adverse events in all vaccinated patients. The key secondary endpoints included prognosis assessed by recurrence-free survival and overall survival rate. Results: We observed only 3 grade ≥3 adverse events in 2 patients (12.5%) and no grade ≥4 events. Vaccinated patients achieved favorable survival outcomes, with a 3-year recurrence-free survival rate of 56% and a 3-year overall survival rate of 74%. Using single-cell sequencing, we revealed the dynamics of vaccine-induced immune responses, with CD8+ cytotoxic T cells expanding at the priming phase and CD4+ T cells at the boosting phase. The CD8+ cytotoxic T cells had a higher proportion (average, 38.4%) of persistent expansion than the CD4+ T cells (average, 3.7%), with a range of 2.8~21.8 months duration. We also discovered a helper B-cell subtype that interacted with T cells and was associated with prognosis, suggesting a role for B-cell epitopes in vaccine effectiveness. Conclusions: These results provide valuable insights for optimizing peptide-based neoantigen vaccine design, regimen, and evaluation strategies. Clinical trial information: NCT03558945 .
Unfolding the role of cell state on stress granule heterogeneity and function in pancreatic cancer.
Authors: Redding Alexandra
Published: July 2024

e16357

Background: A major impediment to cancer therapy is the reality that cancer is a heterogeneous disease. A single tumor can consist of many genotypic or phenotypic profiles, which are marked by degrees of sensitivity to different therapeutics. Identifying and targeting origins of cancer cell heterogeneity is critical for predicting patient outcome and enhancing treatment efficacy. We observe a novel source of cancer cell heterogeneity that involves one of the largest stress-sensing platforms described to date: the stress granule (SG). Stress granules are non-membranous, cytoplasmic organelles that assemble in response to stress, and promote cell survival. Deregulation of SGs has been linked to several pathological conditions, including cancer, neurodegeneration, ischemia, and viral infections. SGs have been shown to promote tumor growth and metastasis, as well as contribute to mechanisms of chemo-resistance. Thus, these signaling hubs are emerging as a potential target in cancer. Methods: To induce SG formation, human pancreatic ductal adenocarcinoma (PDAC) cell lines were treated with sodium arsenite, thapsigargin, or exposed to hypoxic conditions. Immunoflourescent staining of core SG proteins was then conducted. To investigate cell cycle-driven mechanisms of SG heterogeneity, cell cycle stage was identified by expression of a Fluorescent ubiquitination-based cell cycle indicator (Fucci) lentiviral system. To investigate cPLA2’s role in SG formation, the chemical inhibitor Pyrrophenone, an shRNA targeting cPLA2, and an exogenous full-length or cleaved form of cPLA2, were used. In vivo, ES149 cells expressing Luciferase and the Fucci system were orthotopically implanted into C57BL/6 mice. Established tumors were treated every 3 days with Vehicle, Oxaliplatin, Pyrrophenone, or a combination of the latter. Tumor size was tracked via IVIS Spectrum. Fucci flourescence was used to identify cell cycle phase. SGs and cell death were assessed by immunoflourescent staining of tumors. Results: Cancer cells show a high degree of heterogeneity in their production of SGs. Cell cycle phase dictates SG heterogeneity. G2 phase cells have significantly higher levels of SG formation as compared cells in G1/S. This process is regulated by cleavage of the cPLA2 protein. Oxaliplatin administration increases G2 phase content in tumors. Co-treatment with Oxaliplatin and Pyrrophenone significantly decreases SG formation, increases cell death, and leads to tumor regressions in vivo. Conclusions: G2 phase cancer cells develop higher levels of SGs when exposed to stressful stimuli, as compared to G1/S phase counterparts. The cPLA2 protein is cleaved into a catalytically dead form that is present in G1/S phases, but absent in G2 phase. Oxaliplatin treatment in vivo leads to an increase in G2 phase tumor cells. When paired with cPLA2 inhibition, this results in increased cancer cell death and decreased tumor growth.
Circulating tumor DNA for recurrence monitoring following resection for pancreas adenocarcinoma.
Authors: Amini Neda , Koti Shruti , ASCHERMAN BENJAMIN , King Daniel
Published: July 2024

e16365

Background: Detecting early recurrence among patients with resected pancreatic cancer may facilitate earlier treatment and better outcomes for patients with resected pancreatic ductal adenocarcinoma (PDAC). Circulating tumor DNA (ctDNA) has shown promise as a tumor-specific biomarker for PDAC but has not yet entered routine clinical use. This study aims to conduct analytical and clinical validation of Signatera ctDNA profiling to predict recurrence in patients with PDAC. Methods: A retrospective IRB-approved protocol evaluating the use of Signatera ctDNA testing among patients who underwent resection at Northwell Health during 2019-2023. The utility of ctDNA status to predict PDAC recurrence during follow-up was assessed using cox regression. Results: There were 91 ctDNA tests among 24 patients. With a median follow-up of 15 months, recurrence was observed in 38% (9/24) of patients and 8 patients died. Among patients with recurrence, most of them had positive ctDNA before showing signs of recurrence on the imaging (6/9, 66.7%) with mean lead time of 116 days, while 2 of them had positive ctDNA after recurrence and one patient never had positive ctDNA. At the time of recurrence, eight patients had elevated CA19-9, while two patients with normal CA19-9 had positive ctDNA. The median recurrence-free survival (RFS) was 23 months (95% CI, 11-not reached). Patients with detectable preoperative ctDNA had significantly decreased median RFS (14 months; 7 of 10 (70%) recurred) when compared with patients negative for ctDNA [not reached; 2/14 (14.3%) recurred; P= 0.005). In multivariable Cox model after adjusting for potential risk factors, detection of ctDNA was associated with RFS. (table). Conclusions: Signatera ctDNA profiling identified relapse earlier than imaging for most patients. These results suggest the potential for a prospective trial evaluating early treatment interventions in this deadly disease to improve survival rates. [Table: see text]
Association of human interpretable features derived from pancreatic ductal adenocarcinoma pathology slides with disease-free survival.
Authors: Siddiqui Zafar , Haemmerle Robert , Carr Ryan Michael
Published: July 2024

e16368

Background: Pancreatic ductal adenocarcinoma (PDAC) is predicted to be the second cause of cancer death in the US by 2040. For the minority of patients who are candidates for curative-intent surgical resection, a neoadjuvant approach with chemotherapy or chemotherapy followed by chemoradiotherapy (chemoRT) has become the standard of care. The tumor microenvironment (TME) has been recognized as a key factor in therapeutic resistance and disease progression. This study aims to explore the prognostic value of human-interpretable machine learning image features (HIFs) derived from whole-slide H&E images. Methods: Consecutive PDAC patients who underwent neoadjuvant therapy followed by surgical resection were studied in this single-institution retrospective study. Clinical variables collected include tumor site (head/body/tail), surgery extent, histology, sex, age at diagnosis, grade, treatment response (4-point scale), LVI, PNI, resection margin status, pathological TNM staging, number of lymph nodes removed/positive, neoadjuvant strategy (chemotherapy vs chemoRT), and number of neoadjuvant chemo cycles. These factors were analyzed with a multivariable Cox proportional hazards model for disease-free survival (DFS) after surgery. Additionally, 420 human-interpretable image features (HIFs) derived from a commercial machine learning software were analyzed with a univariable Cox model on a binary outcome of 1-yr DFS, applying a Bonferroni correction for multiple comparisons to identify significant predictors. Results: Increased neoadjuvant chemotherapy cycles (HR = 0.62, p = 0.001, [median: 8, IQR: 6-12]) and receipt of combination neoadjuvant therapy (HR = 0.15, p = 0.020, [29% chemo, 71% +chemoRT]) exhibited a protective effect in the multivariable DFS model. 3 HIFs quantifying immune cells and macrophages within the cancerous tissue and its stroma were associated with an improved probability of 1-year DFS. Conclusions: In addition to clinical factors, HIFs may offer valuable insights into the tumor microenvironment's influence on PDAC progression, paving the way for improved prognostic models and therapeutic strategies. Future work will integrate clinical predictors with HIFs in a combined model.
Longitudinal circulating tumor DNA monitoring for detection of molecular residual disease in patients with advanced germ cell tumors.
Authors: Au Cherry , Patel Mukti , Tan Alan
Published: July 2024

e17022

Background: Germ cell malignancies, commonly manifesting as testicular cancer, is one of the most common malignancies in men 15 to 45 years of age, with the incidence doubling over the past 40 years. When identified promptly and treated with a multidisciplinary approach, germ cell tumors have an excellent prognosis with cure rate >90% and 5-year survival rate >95%. Treatment involves radical orchiectomy for diagnostic and therapeutic purposes. Further management includes active surveillance, adjuvant chemotherapy, retroperitoneal lymph node dissection (RLND), and radiation therapy. While AFP, B-HCG, and LDH are good biomarkers, they are not sensitive or specific for detecting molecular residual disease (MRD). B-HCG is detected in <30% of individuals with seminoma and B-HCG and AFP are detected in 50–60% of patients with non-seminomatous tumors. We describe the use of circulating tumor DNA (ctDNA) for detection of MRD in advanced germ cell malignancy, especially when baseline biomarkers are negative. Methods: This is a retrospective analysis of 20 patients with testicular cancer treated at Rush University Medical Center who monitored closely for MRD. Signatera (Natera Inc.), a personalized tumor-informed ctDNA assay, was utilized for detection and quantification of ctDNA in patients’ plasma samples, measured at MRD (1-12 weeks post-orchiectomy) and regular intervals thereafter, regardless of treatment modality. Event free survival (EFS) was determined, defined as the period from radical orchiectomy to date of radiographic progression of disease. Results: There was a total of 20 patients (35% seminoma, 65% non-seminoma) with 2 of the patients having extragonadal disease. The mean age was 32.2 years old with IQR (28-36). Post operatively, 20% underwent RLND, 10% were on surveillance, 53% received post-orchiectomy chemotherapy, 6.7% of patients underwent autologous stem cell transplant. The median follow up time is 1.14 years. Two patients had positive ctDNA despite negative baseline traditional biomarkers. There were 23.3% (7/30) of patients that had evidence of radiographic progression. Of the patients with progression, serial ctDNA monitoring had high rates of concordance (85%, 6/7) of ctDNA positivity with biomarker positivity and radiographic progression. Conclusions: Overall, ctDNA correlated with, and sometimes even preceded, traditional biomarkers and radiographic findings of disease progression. The ctDNA positivity of 2 patients in this cohort despite negative baseline AFP, B-HCG, and LDH, highlights the sensitivity and specificity of ctDNA for MRD compared to more traditional biomarkers. Serial monitoring of ctDNA offers valuable insights into germ cell tumor disease status, including presence of MRD, and there is a need for prospective studies to guide treatment escalation and de-escalation in germ cell tumors.
Xerostomia and ocular dryness as predictors of PSA response to Lu177-PSMA-617 in metastatic castration resistant prostate cancer.
Authors: Hassoun Rebecca , Tann Mark , Sims Justin , Auxier Ashleigh , Althouse Sandra K. , Salous Tareq , King Jennifer , Adra Nabil
Published: July 2024

e17028

Background: Prostate specific membrane antigen (PSMA) is highly expressed in salivary and lacrimal glands. Dry eyes and/or mouth can occur with Lu177-PSMA-617 (PSMA Lu177) therapy in metastatic castration resistant prostate cancer (mCRPC) pts. We evaluated the difference between the presence of dry mouth/eyes with PSA responses in pts with mCRPC treated with PSMA Lu177. Methods: The Indiana University Prostate Cancer database was queried for pts with mCRPC who were treated with PSMA Lu177. Toxicities were documented throughout the course of treatment. Association of xerostomia and ocular dryness with PSA30 and PSA50 response was compared using the Chi Square test, or Fisher’s Exact test, if more appropriate. Results: Between 6/21/22-11/14/23, 107 pts with mCRPC were treated with PSMA Lu177 with at least 2 doses. Median age was 73 (56, 90). 86 pts had metastatic disease in bone, 65 lymph nodes, 11 lungs, 6 liver, and 2 brain. 39 pts had 1 prior ARPI, 68 pts had ≥2 prior ARPI. 17 pts had no prior taxane regimen, 45 had 1 prior taxane, 33 had 2 prior taxanes and 12 had ≥3 taxane regimens. 19 pts had prior PARP inhibitor. Median follow-up from start of PSMA Lu177 treatment was 8.3 months (1.4-18.7). 40 (37%) pts experienced dry mouth, 7 (7%) pts experienced dry eyes, and 6 (6%) pts experienced both. 65 (61%) pts achieved PSA30 response. 57 (53%) pts achieved PSA 50 response. Conclusions: The presence of dry eyes and/or dry mouth in pts with mCRPC treated with PSMA Lu177 was associated with improved PSA response. [Table: see text]
Real-world treatment landscape in advanced metastatic castration resistant prostate cancer.
Authors: Sacchi Elizabeth , Singhal Hari , Zamalloa Jose , Lopez Sanchez Beatriz , Zhang Ke , Parihar Harish , Greshock Joel , Max Steven I
Published: July 2024

e17032

Background: Despite a rapidly evolving treatment landscape in advanced prostate cancer (aPC) marked by recent emergence of therapies such as radioconjugates and PARP inhibitors, outcomes remain poor for many patients. Future care improvements will require innovative treatments and simplifying treatment planning. The goal of this study is to understand how the evolving treatment landscape has impacted care and outcomes in patients with aPC using real world (rw) data. This study evaluates outcomes of mCRPC patients who have advanced to a 3rd line of therapy (L3) with prior exposure to both an androgen receptor signaling inhibitor (ARSI) therapy and a taxane or platinum-based chemotherapy, in any aPC disease setting. Methods: mCRPC patients in the Flatiron Database who progressed to L3 with pre-L3 exposure to both an ARSI (abiraterone, enzalutamide, apalutamide, and darolutamide) and chemotherapy (cabazitaxel and docetaxel) were eligible for inclusion. Patients whose mCRPC diagnosis occurred between Dec 2010 and Nov 2023 were included. As the objective was to study the aPC treatment landscape, patients with prior exposure to therapies approved in the mCRPC disease setting such as radioconjugates, PARP inhibitors, radiation, investigational and palliative drugs were excluded. Outcomes were reported as median real-world overall survival (rwOS) indexed to start of L3 treatment, and median rw time to next treatment (rwTTNT) from the start of L3 to the beginning of L4 treatment. Results: 660 patients met all inclusion criteria and had at least one year of treatment history in the aPC disease setting. Median follow up time (indexed to L3 start) for all patients was 7.55 months. Median rwOS for all patients was 10.8 months (95% CI 9.9 - 12.2), while median rwTTNT was 5 months (95% CI 4.6 - 5.4). The most common L3 therapy class was chemotherapy, followed by ARSIs (Table). To aid in treatment planning strategies, drug sequence patterns were also analyzed. Frontline ARSIs were followed by second line chemotherapy for most of the patients (n = 349; 53%). Conclusions: Relatively short survival times and short durations on L3 therapies for aPC demonstrate a high unmet need, with therapeutic options dominated by ARSIs and chemotherapy. Recently approved radioconjugate therapies, like Pluvicto â, have reported median OS 15.3 months (Fallah, 2023) in prostate-specific membrane antigen (PSMA)-positive patients, which is greater than the 10.8 months observed in general mCRPC population analyzed in this study. These findings underscore the need to develop effective therapies and treatment strategies that are tailored for advanced prostate cancer. [Table: see text]
Outcome of prostate cancer with CNS metastasis: An analysis of SEER database (2010-2020).
Authors: Lee Hyun , Mei Lin , Baralo Bohdan , Poklepovic Andrew Stewart , Paul Asit K.
Published: July 2024

e17037

Background: Brain metastasis from prostate cancer is rare, with an estimated incidence of <1%, and its characteristics and outcomes are poorly understood. We report a contemporary analysis of outcomes in patients with CNS metastasis from prostate cancer in association with clinicopathological variables by utilizing the Survival, Epidemiology, and End Result (SEER) database with data from 2010 to 2020. Methods: From the SEER database, we identified histologically confirmed primary prostate cancers with any distant metastasis. Data for survival as well as multiple clinicopathological variables including age, race, prostate-specific antigen (PSA) level, Gleason score, prior radiotherapy, histology, and specific metastatic sites were extracted. Statistical analysis included chi-square. ANOVA, and Kaplan-Meier analysis for overall survival (OS) and disease-specific survival. Results: SEER database (2010-2020) identified 27,501 patients with metastatic prostate cancer, of which 27,118 (98.6%) were adenocarcinoma and 383 (1.4%) were prostate cancer with neuroendocrine features. Brain metastasis was seen in 282 (1.04%) and 15 (5.32%) patients in these histologic groups, respectively. Brain metastases were associated with worse prognosis with median OS of 14 months compared to bone-dominant and non-regional lymph node only diseases that showed median OS of 31 months and not reached, respectively (P < 0.01). Within the population with brain metastases, outcome comparison based on age (<65 vs. ≥65 years), ethnicity (Caucasian vs. African American vs. Hispanic), PSA (<98 vs. ≥98 ng/ml), and Gleason score (<9 vs. ≥9) showed no statistically significant difference (table). Presence of metastasis to other solid organs showed numerically worse outcome without statistical significance (OS: 26 months vs. 13 months, p=0.09). Significant OS difference was observed between the adenocarcinoma and neuroendocrine tumor within the brain metastasis subgroup (OS: 14 months vs. 6 months, p=0.03). Conclusions: CNS metastasis with prostate cancer carries worse prognosis in comparison to metastases to bone or distant lymph-nodes. Neuroendocrine tumor has higher risk of CNS metastasis although most of such cases are from adenocarcinoma due to its higher prevalence. OS analysis confirms worse outcome with neuroendocrine features compared to adenocarcinoma in CNS metastatic settings. [Table: see text]
Clinical–epidemiological characterization of cervical cancer in a middle-income country.
Authors: Morquecho Walter , Argüello Mario , Reyes José Luís , Pulla Fausto Emiliano , Ávila Víctor Hugo , Estrada Lorena Paola , Paulson Guillermo , Santacruz Mayra
Published: July 2024

e17514

Background: Despite significant advances in prevention and treatment, cervical cancer remains a global public health threat, claiming the lives of hundreds of thousands of women each year. It disproportionately affects women in low- and middle-income countries, where access to vaccination, screening, and early diagnosis is often limited. The present study aims to determine this pathology's clinical and epidemiological characteristics. Methods: This is an observational, descriptive, retrospective, and cross-sectional study. Information from the digital medical records of patients with cervical cancer from SOLCA Guayaquil from January 2010 to December 2014 was used. Results: 1909 medical records of patients with cervical cancer were reviewed during the study period; 211 were excluded for not meeting eligibility criteria, leaving 1698 to be evaluated. Regarding stages (I-II-III-IV), the most frequent was stage II (A-B), 54.2% of them, squamous cell carcinoma (44.6%), and adenocarcinoma (9.6%). 32.2% correspond to resectable cancers (IA-IIA), and 67.8% to non-resectable cancers. The mean age was 55 years, the median was 54, and the mode was 45. The absence of these comorbidities was the most frequent (47.8%), then kidney (6%) and ureteral (4.7%). Conclusions: The age of presentation of cervical cancer in this health center is higher than the global average but closer to what is seen in Latin America. The clinical stages are relatively advanced at diagnosis. The most frequent histopathological types were squamous cell carcinoma and adenocarcinoma. What predominated was the absence of comorbidities. [Table: see text]