bluuebunny/crossref_metadata_2025 huggingface dataset:
Survival outcomes in patients with advanced intrahepatic cholangiocarcinoma in United States: A nationwide analysis.
Authors: Jayram Diya , Aziz Nouman , Naeem Hamza , Ahmad Shahzaib , Chaudhary Muhammad Ahsan Hanif , Bellur Shreyas S. , Ganiyani Mohammad Arfat , Ayoobkhan Fathima Shehnaz , Ahluwalia Manmeet Singh
Published: July 2024

e16211

Background: Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver malignancy after hepatocellular carcinoma. Anecdotal evidence shows that chemotherapy and radiotherapy after surgical resection confer better survival outcomes in patients with advanced disease. This study aims to demonstrate outcomes of different therapeutic options in patients with stage 4 ICC. Methods: We queried the National Cancer Database from 2004 to 2020 to identify patients with stage 4 ICC. The study compared median overall survival (mOS) using Kaplan-Meier methodology and pair-wise log-rank test among different therapeutic groups, including surgery (Sx) alone, chemotherapy (CT) alone, radiotherapy (RT) alone, surgery + chemotherapy (Sx+CT), surgery + chemoradiation (Sx+CRT), and chemoradiation (CRT). The results of the study were reported in concordance with STROBE guidelines. Results: Among 13,735 patients with stage 4 ICC, the median age was 64 years (range: 17-90+ years), 51.0% were male, 83.6% were White, 9.1% Black and 4.0 % Asian. 342 (2.5%) underwent Sx, 10061 (73.3%) CT alone, 427 (3.1%) underwent RT alone, 744 (5.4%) Sx+CT, 314 (2.3%) Sx+CRT, and 1847 (13.5%) underwent CRT. Patients who underwent Sx+CRT had better mOS (23.8 months, 95% CI 20.5-24.1) than all other modalities, including Sx (11.1 months, 95% CI 8.2-13.4), CT (8.6 months, 95% CI 8.4-8.9), RT (4.7 months, 95% CI 3.8-5.2), Sx+CT (21.9 months, 95% CI 20.0-24.1) and CRT (11.7 months, 95% CI 11.1-12.3) p < 0.01. Conclusions: Unlike other gastrointestinal malignancies, multimodal therapy i.e., chemoradiation after surgical resection of primary tumor improves survival in advanced ICC. However, prospective studies affirming these findings are warranted.[Table: see text]
Predictors of good outcomes in patients with hepatocellular carcinoma (HCC) treated with transarterial radioembolization (TARE).
Authors: Das Parthib , Paul Samuel , Min Eric , Mittra Arjun , Malalur Pannaga G. , Manne Ashish
Published: July 2024

e16219

Background: No reliable biomarkers or risk factors guide treatment selection in HCC patients. Management is typically institution-specific, and compliance with the available guidelines is low. Our retrospective review aims to identify HCC patients suitable for TARE. Methods: HCC patients treated with TARE between 1/1/2015 and 8/30/22 at Ohio State University were included in this study. Patient-related information was extracted from chart review. Various risk factors (related to HCC and TARE) were compared between good (GR) and poor (PR) responders (progression-free survival (PFS) ≤ vs. > median (m)), and good (GSv) and poor (PSv) survivors (overall survival (OS) ≤ vs. > m). Chi-square test and logistic regression were performed using JMP Pro 17 (SAS Institute Inc., Cary, NC). Results: Our cohort included 141 patients. The median age was 65 years (range 49-88), 80% were males and 80% were White (16% were African American and 4% were other). The median OS and PFS were 9 months (m) (95% confidence interval [CI], 5-22.5) and 4m (95% CI, 2-9), respectively. Compared to PSv (OS ≤ 9m, N = 71), the GSv group (OS > 9m, N = 70) had a high alcohol history (hx) (64% vs. 44%, p = 0.01); less baseline (BL) encephalopathy (Enc) (21% vs. 37%, p = 0.04) and post-TARE ascites (As) (31% vs. 63%, p = 0.001); were able to receive immune-checkpoint inhibitor (ICI) (44% vs. 6%, p < 0.001) before (6% vs. 1%) or after (39% vs. 10%) TARE. Other key BL features with a trend to significance (p = 0.06-0.08) were less BL cirrhosis (69% vs. 87%) and As (19% vs. 34%), hx of HCC treatment (systemic or local, 43% vs, 28%), and ability to get second TARE (19% vs. 8%). In worse survivors (PFS ≤ 5m, N = 40), post-TARE As (65% vs. 41%, p = 0.008) was significantly higher. Only 2/40 patients were able to get ICI (95% vs. 37%, p = 0.0002) in this group. Compared to PR, the GR group (PFS > 5m, N = 64) had a higher rate of diabetes mellitus (DM) (45% vs. 26%, p = 0.02) and less post-TARE As (34% vs. 58%, p = 0.004). BL and HCC-related factors prominently NOT featured in these comparisons were hepatitis (B or C) or smoking hx and macrovascular invasion. Conclusions: TARE suits patients with hx of alcohol use or DM, no BL Enc, As, or cirrhosis, and failed prior lines. Post-TARE As is poor prognostic markers. ICI use will improve the outcomes.
An open-label, placebo-controlled, randomized phase II trial of camrelizumab combined with or without apatinib or capecitabine in the treatment of previously treated advanced pancreatic cancer.
Authors: Chen Jianhua , Liu Jun , Li Ning , Huang Weiyi , Chen Donghui , Tao Wei , Wang Hongxia
Published: July 2024

e16324

Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the few cancer types that have essentially no clinical benefit from immune checkpoint inhibitors therapy, combined immunotherapy is expected to solve this dilemma. We conducted a randomized open-label, placebo-controlled phase II trial evaluating the efficacy of camrelizumab combined with apatinib or capecitabine in the treatment of patients with previously treated metastatic PDAC (ChiCTR1900024095). Methods: Eligible patients (n = 30) were randomized 1:1:1 to receive camrelizumab (200 mg q2w) combined with apatinib (250mg qd, d1-28, q4w) or capecitabine (1000 mg/m2, bid d1-14, q3w), or placebo plus capecitabine (1000 mg/m2, bid d1-14, q3w) until disease progression or unacceptable toxicity. Tumor response was assessed every 8 weeks according to RECISTv1.1. Primary endpoints were investigator-assessed 6-month overall survival (OS) rate. Secondary endpoints were progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), duration of response (DoR) and safety. Data cutoff date for the prespecified interim OS and final PFS analysis was Oct 30, 2022. Results: In the primary endpoint analysis, camrelizumab combined treatment showed improved 6-month OS rates, whether in the camrelizumab-apatinib arm (83.3% versus 33.3%, p = 0.1189) or in the camrelizumab-capecitabine arm (100% versus 33.3%, p = 0.0098), compared placebo-capecitabine, respectively. Median PFS was 5.4 months, HR 0.58, [95% confidence interval (CI), 0.21–1.59] in the camrelizumab-apatinib arm , 3.1 months HR 0.98, [95%CI, 0.35–2.77] in the camrelizumab-capecitabine arm , and 2.6 months in the placebo-capecitabine, respectively. The ORR and DCR were 0% and 66.7% in the camrelizumab-apatinib arm, 40% and 50% in the camrelizumab-capecitabine arm, 0% and 44.4% in the placebo-capecitabine, respectively. PR was observed in two patients receiving camrelizumab-capecitabine treatment. The median DoR were 5.3 months in the camrelizumab-apatinib arm, 4.3 months in the camrelizumab-capecitabine arm, and 2.1 months in the placebo-capecitabine arm. Treatment-related adverse event rates were slightly increased in camrelizumab combined arms. Incidences of grade ≥3 treatment-related adverse events were comparable between the three groups (20%、 10% vs 0%), with reactive cutaneous capillary endothelial proliferation (10%) as the most common one in Camrelizumab combinations. Conclusions: Camrelizumab combined treatment showed improved 6-month OS vs conventional capecitabine monotherapy, with a manageable safety profile. These analyses revealed combined immunotherapy could be used as a new option for posterior line treatment in previously treated metastatic PDAC. Clinical trial information: ChiCTR1900024095.
ITGB6 as an inhibitor of T-cell killing via modulation of paracrine TGFβ signaling in pancreatic ductal adenocarcinoma.
Authors: MacDonald William J. , Schwermann Maximilian , Srinivasan Praveen , Tajiknia Vida , El-Deiry Wafik S.
Published: July 2024

e16334

Background: Immunotherapy has experienced limited success in PDAC, with αPD-1 therapy being approved only in a subset that makes up < 2% of all PDAC cancers. TGFβ is a contributor to T-cell suppression in the PDAC tumor microenvironment. However, the success of blocking TGFβ in preclinical models has failed to translate into the clinic due to the off-target effects of systemic TGFβ blockade. Integrin ITGB6 is an activator of the inert latent TGFβ into the active, immunosuppressive form. Consequently, inhibition of ITGB6 is a potent and targeted therapeutic approach for disrupting TGFβ to overcome T-cell suppression in PDAC. Methods: Analysis of TCGA molecular and survival data was performed to determine the specificity and prognostic value of ITGB6 in PDAC. Subsequently, candidate cell lines were screened for ITGB6 expression using flow cytometry to facilitate an in vitro model. Using a lentiviral system, PDAC cells were transduced with a doxycycline-inducible short hairpin RNA (shRNA) knockdown (KD) of ITGB6. Both KD and control shRNA cell lines were induced with doxycycline and subsequently co-cultured with TALL-104 T-cells. Furthermore, conditioned media was analyzed for secreted active TGFβ levels using a luciferase-based TGFβ reporter cell line. Finally, a clonogenic assay was performed to determine the autocrine effects of TGFβ activation in PDAC. Results: ITGB6 is highly specific to PDAC and also shows upregulation in comparison to normal pancreatic tissue (FC 3.38, p < 0.0001). Capan-2 cells were chosen as a model for high integrin PDAC (Capan-2 99.73% cells ITGB6+, negative control: HCT116WT 0.96% cells ITGB6+). Fluorescent microscopy of the co-culture revealed that the KD of ITGB6 increased T-cell killing over 24 hours (Capan-2 CTRL shRNA 7.71%±3.63 dead vs. Capan-2 ITGB6 shRNA 21.68%±4.57 dead, p < 0.05). Media from ITGB6 KD cells contained significantly decreased TGFβ (+TGFβ: 673000 RLU vs. CTRL: 175500 RLU, p = 0.015). A clonogenic assay of Capan-2 cells treated with active-TGFβ demonstrates that PDAC cells resist the autocrine growth inhibitory effects of TGFβ through loss of SMAD4. TCGA survival data revealed ITGB6 as prognosis marker in PDAC (high ITGB6 median survival 16.79 mos, vs. low ITGB6 21.88 mos, HR = 2.730, p < 0.004). Conclusions: Survival data that clearly demonstrates the poor prognosis of ITGB6 expression, as well as the presently proposed mechanism of immunosuppression, provide ample justification for deploying anti-ITGB6 combination therapies to in vivo studies that facilitate translation of our findings into therapeutic clinical trials.
Pluvicto in the real world setting and timing to PSA50 as a predictive marker of treatment response.
Authors: Maslov Diana Vesselinovitch , New Jacob , Patel Nikunj , Kosty Michael P. , Bhangoo Munveer Singh
Published: July 2024

e17026

Background: Prostate cancer, the leading cause of cancer mortality in men, has seen notable advances with PSMA-targeted therapies like 177Lu-PSMA-617 (Pluvicto), particularly in the metastatic castrate resistant setting. While prostate specific antigen (PSA) serves as a useful biomarker in newly diagnosed patients or those on androgen deprivation therapy, its efficacy in monitoring patients under PSMA-directed therapy remains unclear. This underscores a critical gap: the absence of established biomarkers for tracking response to these emerging treatments. Such biomarkers are vital for enhancing patient outcomes and evaluating therapeutic efficacy in early-stage trials. Methods: In this real-world, cohort study, we retrospectively followed adult patients with metastatic, castrate-resistant prostate cancer who are treated with Pluvicto at our institution beginning January 1, 2022 through November 2023. We assessed several potential biomarkers of response temporally throughout the treatment duration of Pluvicto, including serial blood counts, chemistry profiles, PSA levels, BMI, as well as their historical treatment patterns and demographics. All patients were heavily pre-treated prior to receiving Pluvicto. By using logistic regression, we identify factors associated with treatment response. Results: In our study, 21 patients qualified for enrolment. These patients received a median of 6 treatments prior to Pluvicto. Among them, 8 (38.1%) demonstrated at least PSA50 and showed response post-treatment. Of these, 6 (75%) completed all six Pluvicto treatments, while 2 (25%) are currently undergoing treatment. Remarkably, 7 of the 8 responders (87.5%) achieved a PSA50 response after two Pluvicto doses, with all 8 (100%) reaching this marker by the third dose. Furthermore, 6 of these 8 patients (75%) exhibited a PSA90 response after the fourth dose, though 2 patients (25%) did not attain PSA90. Conclusions: Our real-world study at Scripps Clinic provides valuable insights into the efficacy of Pluvicto in treating metastatic, castrate-resistant prostate cancer. Out of 21 patients treated with Pluvicto, 38.1% exhibited a significant PSA decrease during the treatment course. Notably, 87.5% of responders achieved PSA50 before their third dose, and all responders reached this benchmark prior to their fourth dose. These findings are crucial, especially as clinical trials are exploring Pluvicto's application in earlier treatment stages. Additionally, the use of PSA50 as a biomarker could guide clinicians in timely decision-making, allowing for quicker intervention and therapy adjustments, thus potentially mitigating disease progression. Updated data to be presented.
Evaluation of malignant potential based on infection with high-risk human papillomaviruses 16, 52, and 58 in the uterine cervix.
Authors: Lee Seung-Mi , Lee Hyun-Jung , Lee Juhun
Published: July 2024

e17511

Background: The high-risk human papilloma virus (HR-HPV) has been known as the most important carcinogen in uterine cervical carcinoma. Generally, gynecologists recommend medical interventions for patients diagnosed with HSIL or higher. Previous studies have evaluated genotype-specific risk for carcinogenesis. However, the genotype-specific risk remains still unclear due to some limitations of those studies. This study aimed to evaluate the malignant potential of the three most prevalent HR-HPVs in Korea. Methods: Patients who underwent uterine cervical conization were included. They had received HPV test within a year before the surgery and those exhibiting concurrent multiple infections with HR-HPVs were excluded. Of single infections with HR-HPV, the three most prevalent HR-HPVs were included to analyze. To evaluate their malignant potential, CIS+, including carcinoma in situ (CIS) and invasive carcinoma, was categorized in each HR-HPV group. The ratios of pathologic diagnoses and odds ratios for malignant potential were evaluated between the three most prevalent HR-HPVs. Results: Totally 230 patients were found to have a single infection with HR-HPV16, HR-HPV52, or HR-HPV58. Of the included patients, 119 (51.7%), 60 (26.1%), and 51 (22.8%) were noted to be infected with HR-HPV genotypes 16, 52, and 58, respectively. CIS was diagnosed in 59 (49.6%), 27 (45.0%), and 25 (49.0%) patients in the HPV16, HPV52, and HPV58 single infection groups, respectively ( p = 0.839). Invasive carcinoma, regardless of histology such as squamous cell carcinoma or adenocarcinoma, was diagnosed in 8 (6.7%), 1 (1.7%), and 1 (2.0%) patient in the HPV16, HPV52, and HPV58 single infection groups, respectively ( p = 0.187). The CIS+ ratio was not significantly different among the HPV16, HPV52, and HPV58 single infection groups (67 [56.3%] vs. 28 [46.7%] vs. 26 [60.0%], [ p = 0.460]). Conclusions: Among the Korean women with single HR-HPV infection, HPV16, HPV52, and HPV58 were the three most common genotypes, in descending order. Although HPV16 was the most prevalent among the three, its malignant potential was not significantly different from those of HPV52 and HPV58 in the uterine cervix. This result supports the need for a nine-valent vaccine against HR-HPVs, covering HPV52, HPV58, and HPV16.
A study of risk factors and clinico-pathological profile of patients with cervical cancer at BPKIHS: A descriptive cross-sectional study.
Authors: Shrestha Ramesh
Published: July 2024

e17515

Background: Cervical cancer is the cancer with highest incidence and mortality among females in Nepal according to GLOBOCAN data 2020. The aims of this study was to evaluate the risk factors and clinico-pathological profile of patients with cervical cancer attending Department of Gynaecology, BPKIHS, Dharan, Nepal. Methods: It was a descriptive cross-sectional study conducted from April, 2019 to February, 2022 among seventy-nine patients with histological diagnosis of cervical cancer after ethical approval. Results: The mean age of these patients was 54.99±12.81 years. The commonest presenting symptom was postmenopausal bleeding (65.8%) and the commonest histological type was squamous cell carcinoma (87.3%). The commonly associated risk factors among them were illiteracy (88.6%), poor local hygiene (78.5%), postmenopausal status (72.2%) and poor socio-economic status (41.8%). The mean age at marriage and first pregnancy were 18.45 (SD=2.32) years and 19.47 (SD=2.51) years respectively. More than one-fourth (29.1%) of the patients had more than or equal to 5 children. Only three (3.8%) patients had undergone cervical cancer screening once in their lifetime.Most of them (n=66; 83.5%) had locally advanced disease at diagnosis. Altogether, sixty-seven (84.8%) patients were referred outside for radiation treatment. Among the surgically treated patients, twelve (63.2%) patients subsequently required dual treatment. Conclusions: Illiteracy, poor hygiene, low socio-economic status, patient’s delays, poor screening programmes, multiparity, early age at marriage and first child birth etc. are the factors requiring major focus to reduce the burden of cervical cancer in developing countries like Nepal.
Real-world data of a regimen containing zimberelimab in the treatment of recurrent and metastatic cervical cancer.
Authors: Tian Qiuhong , Xu Qin , Li Fan , Huang Jin , Liu Jing , Zang Lele , Ting Li , He Lianxiang , Yang Wenhan
Published: July 2024

e17521

Background: Cervical cancer is the malignant tumor in women. Zimberelimab is approved by NMPA for PD-L1 positive recurrent and metastatic cervical cancer. However, no real-world data of zimberelimab in recurrent and metastatic cervical cancer have been reported before. Methods: From August 2021 to March 2023, we retrospectively collected patient data at the First Affiliated Hospital of Nanchang University and Fujian Cancer Hospital. Patients with advanced or recurrent cervical cancer who had been pathologically diagnosed were eligible, regardless of whether they had squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma and PD-L1 status. All patients were treated with regimen containing zimberelimab. Date of brith, previous medical history, tumor stage at first diagnosis, metastatic sites, pathological type, HPV infection and PD-L1 expression status, and treatment regimen containing zimberelimab will be recorded. The primary endpoint was objective response rate and disease control rate assessed by RECIST1.1. The study has been approved by the First Affiliated Hospital of Nanchang University Ethics (No 317). (ChiCTR2300078205). Results: A total of 34 patients were eligible for evaluations of efficacy. 21 from the First Affiliated Hospital of Nanchang University and 13 from the Fujian Cancer Hospital. The median age was 53.23 years (range, 37–66). The ECOG PS was 1 for 23 cases (67.65%), 2 for 10 cases (29.41%).3 for 1 case (2.94%). Squamous cell carcinoma (28,82.35%) was the most common pathological subtype, and the most metastatic site were lymph node (26,76.47%), lung (10,29.41%), bone (6,17.65%), liver (1,2.94%), vulva (1,2.94%), peritoneal (1,2.94%) and bladder (1,2.94%). 32(94.12%) and 30(88.24%) patients have not test for PD-L1 statue or HPV infection. The best overall response of each patient was recorded to evaluate the efficacy. The objective response rate (ORR) in 34 patients were 52.94%, and the disease control rate (DCR) were 97.06%. And 25 patients had previously had ≥1 chemotherapy, and they was treated with a zimberelimab-based combination regimen. The ORR and DCR for these individuals were 52% and 96%, respectively. Conclusions: This is the first report of real-world data on zimberelimab, and zimberelimab combination therapy demonstrated quite good efficacy in patients with recurrence and metastatic cervical cancer who had previously received chemotherapy. Clinical trial information: ChiCTR2300078205. [Table: see text]
Patterns of pembrolizumab use for recurrent cervical cancer.
Authors: Huang Yongmei , Yoh Katherine , Szamreta Elizabeth A. , Xu Xiao , Hershman Dawn L. , Wright Jason Dennis
Published: July 2024

e17528

Background: Pembrolizumab was approved for treatment of recurrent or metastatic cervical cancer (CC) as a single agent after chemotherapy in 2018 and in combination with chemotherapy in 2021, but little is known about how it has been actually used in clinical care. We examined real-world use of pembrolizumab for recurrent CC. Methods: The Merative MarketScan Research Databases were used to identify newly diagnosed CC patients who underwent primary hysterectomy or radiation between 2017-2022. Utilization of systemic therapy was assessed at the time of primary/adjuvant therapy and at first recurrence. Primary/adjuvant chemotherapy was defined as the use of chemotherapy within 4 months of the first cancer claim. First-line (1L) systemic therapy for recurrence was defined as the introduction of a new agent after a gap of > 3 months for patients who received adjuvant/primary chemotherapy or after 4 months from primary hysterectomy or radiation. Treatment for recurrence was classified as platinum alone, platinum-based combination therapy and non-platinum therapy. The use of targeted therapy (bevacizumab) and immunotherapy (pembrolizumab, nivolumab) was noted. Patterns and duration of use of each agent are described. Results: A total of 2727 patients were identified, including 1259 (46.2%) who underwent primary hysterectomy and 1468 (53.8%) treated with primary radiotherapy. Chemotherapy for recurrent CC was initiated in 339 patients (12.4%). Treatment for recurrence was noted in 9.7% of those treated initially with hysterectomy and in 14.8% of those with primary radiotherapy. Among patients treated for recurrence, 24.8% received platinum alone, 52.5% received a platinum-based combination, and 22.7% received non-platinum regimens. A total of 41 patients (12.1%) received pembrolizumab after recurrence, including 7.1% who received pembrolizumab alone, 2.1% who received pembrolizumab in combination with platinum, and 2.9% who received pembrolizumab with non-platinum therapy. Pembrolizumab was used after recurrence in 15.7% of patients who received chemotherapy during primary therapy compared to 7.1% of those who did not receive primary chemotherapy. Use of pembrolizumab was 11.4% in 2018, 17.6% in 2019, 14.0% in 2020, 8.8% in 2021, and 11.8% in 2022. The median duration of 1L chemotherapy for recurrence was 2.3 months (IQR, 1.0-5.8) overall, and 4.3 months (IQR, 2.4, 9.8) for patients treated with pembrolizumab. Patients who had not received primary/adjuvant chemotherapy had a longer duration of treatment with pembrolizumab than those who had received upfront chemotherapy, median 7.5 (IQR 3.9-9.8) versus 4.0 (IQR 2.2-11.0) months, respectively. Conclusions: Platinum-based chemotherapy remains the predominant therapy for recurrent CC. Pembrolizumab use is increasing for patients with recurrent cervical cancer. Longer follow-up is necessary to further evaluate its post-approval usage.
Molecular characteristics of non-human papillomavirus driven cervical adenocarcinoma and adenosquamous carcinoma.
Authors: Lai Chyong-Huey , Lin Chiao-Yun , Wu Ren-Chin , Chao Angel
Published: July 2024

e17532

Background: Cervical cancer is the fourth most common malignancy in women worldwide. Although infection from human papillomavirus (HPV) has been the major cause of cervical cancer, about 3-8% of cervical cancer cases are HPV-negative. Clinical data showed that patients with HPV-negative cervical cancer had significantly lower DFS than those with HPV-positive cervical cancer. The detection of HPV DNA tends to be lower in adenosquamous carcinoma (AC/ASC) than in squamous cell carcinoma. Because the mechanism of HPV-negative cervical cancer development is unclear, this study aims to find the pattern of differential gene expression in HPV-negative AC/ASC and verify the underlying potential mechanism. Methods: In this study, we aimed to exam the differential gene expression profiling by exome-capture RNA sequencing on formalin-fixed, paraffin-embedded tumor tissue of prospectively enrolled cervical AC/ASC patients (HPV-negative: HPV-positive: 1:1) and validate the selected biomarkers on the remaining (unmatched; n = 110) prospective cohort and the 274 retrospective cohort patients. Subsequently, dysregulated differentially expressed genes specifically existed in HPV-negative cervical AC/ASC tissues and HPV-negative cell lines were validated by Western blotting, enzyme-linked immunosorbent assay (ELISA), and immunohistochemical staining (IHC staining). Results: Exome-capture RNA sequencing on HPV-negative and age/grade matched HPV-positive AC/ASC (10:6) for discovery initially. We found differentially activated WNT pathway from HPV positive/negative AC/ASC in the prospective cohort. In the preliminary results of 28 prospective cohort patients, SOX17 and MMP7 highly expressed genes in HPV-negative (n = 13) then the HPV-positive (n = 11) cervical AC/ASC by IHC staining (p = 0.1029 and p = 0.0306, respectively). Moreover, plasma MMP7 levels were upregulated in HPV-negative AC/ASC (n = 10) compared with HPV-positive AC/ASC (n = 17) (p = 0.0086) by ELISA analysis in the prospective cohort. Conclusions: Further studies and more analyses will be continued to investigate the effects of changes in the expression of SOX17 and MMP7 related mechanisms, and targeting WNT/SOX17/MMP7 pathways specifically associated with HPV-negative AC/ASC to provide new insights into the early screening and effective treatment of HPV-negative AC/ASC.
Multi-dimensional measurements of long-term quality of life and recovery patterns of patients with cervical cancer after treatment.
Authors: Qiu Ling , Zhu Shurong , Wang Hui , Feng Hao , Luo Shen , Yang Xiaoyi , Hou Yingchun , Zhang Tao , Zhao Junda , Qiao Danze , Du Yan , Jiang Hua , Wu Xin
Published: July 2024

e17533

Background: Cervical cancer is a prevalent malignancy affecting the female reproductive system globally, and its incidence among younger individuals is on the rise. This study employed the CC-PRO137 scale to evaluate the long-term quality of life and recovery patterns of cervical cancer patients post- treatment. Clinicians are guided to provide individualized treatment and psychological support. Methods: This study recruited patients with primary cervical cancer who underwent primary surgical treatment at the Obstetrics and Gynecology Hospital of Fudan University from October 2018 to June 2021. The CC-PRO137 (Cervical Cancer Patient Reported Clinical Outcome Assessment Scale) was used for follow-up to assess changes in the patients' physical, psychological, and social life states. The data was analyzed to examine variations in the recovery status of the patients across 13 modules: urinary function (URI), bowel function (BOW), pelvic organ prolapse (POP), ovarian function (OVA), lymphatic function (LYM), nervous function (NEU), sexual function (SEX), anxiety (ANX), depression (DEP), shame (SHA), belief (BEL), social support (SUP), and daily life (LIF). Subgroup analysis was conducted based on different stages, surgical methods, and adjuvant treatment plans. Results: A total of 304 participants were tested both 6 months and 12 months after the completion of treatment. The scores for URI, NEU, and SEX were significantly higher after one year compared to within 6 months (URI: t=-3.519, p=0.001; NEU: t=-2.138, p=0.033; SEX: t=-2.338, p=0.021). This suggests a notable improvement in urinary function, nervous function, and sexual function after 12 months. In terms of the psychological domain, DEP scores were significantly higher after 12 months compared to within 6 months ( t=-2.517, p=0.012). The LIF index showed a significant improvement after 12 months ( t=-5.224, p<0.001). Subgroup analysis revealed that Stage II had worse outcomes compared to Stages I and III, particularly in terms of URI ( F(2,297) = 10.619, p < 0.001) and POP ( F(2,299) = 8.559, p< 0.001) indexes. The laparoscopy had a greater impact on the urinary system ( t = 2.157, p = 0.046). The adverse effects of concurrent chemoradiotherapy on URI ( F(2,297) = 11.497, p < 0.001) and DEP ( F(2,299) = 4.149, p = 0.017) functions were more significant than those of chemotherapy. Conclusions: The recovery of patients following cervical cancer treatment is primarily observed in improvements in urinary, bowel, and nervous functions in the physiological domain. In the psychological domain, there is a noticeable improvement in depressive state, while the social life domain also shows signs of improvement over time. By focusing on the disease impact within a limited time frame, the scale helps clinicians provide targeted guidance and advice based on the main issues.
An open, prospective, single arm, phase II study of cadonilimab (PD-1/CTLA-4 bispecific antibody) with neoadjuvant chemotherapy in patients with advanced ovarian cancer: Interim analysis from the AK104-IIT-003 study.
Authors: Tang Jie , Tian Wenfang , Huang Si , Yang Jun , Yang Hongying , Zhang Jieqing
Published: July 2024

e17552

Background: There is an unmet need to improve neoadjuvant chemotherapy (NAC) to decrease postoperative residual disease (R0 rate: 50%) and improve prognosis in ovarian cancer (OC). R0 rate and histopathological response of interval cytoreductive surgery (IDS) after NAC combined with immune checkpoint blockades were reported to be encouraging. Cadonilimab (AK104) is a tetravalent bispecific antibody targeting PD-1 and CTLA-4. In this study, we report the efficacy and safety of AK104 with NAC in patients with advanced-stage ovarian cancer (NCT05430906). Methods: This study is an open-label, prospective, single arm, phase II study of evaluating the efficacy and safety of cadonilimab combined with chemotherapy as neoadjuvant treatment for advanced ovarian cancer. Patients received neoadjuvant therapy of cadonilimab plus platinum-taxane chemotherapy (3 to 4 cycles) followed by surgery. Surgery would be performed within 30 days of completion of neoadjuvant therapy. The primary endpoint was the R0 rate. The secondary endpoints included objective response rate (ORR), disease control rate (DCR), chemotherapy response score (CRS), pathologic complete response(pCR), progression-free survival (PFS), and safety. A sample size of 35 achieves 80% power to detect a difference of 0.2 using a two-sided Z-test to estimate the standard deviation with a significance level (alpha) of 0.1. And the sample size was expected to be 40 cases to ensure that the FAS set contains 35 cases for analysis. Results: 17 patients were enrolled from Dec 12, 2022, to Dec 6, 2023. The median patient age was 57 years (range 45–70 years), and most patients presented with high-grade serous carcinoma (94.1%) and stage IVa (5.9%), IVb disease (76.5%). 15 (88.2%) patients had undergone IDS, with an R0 resection rate of 66.7%. ORR was 94.1%, with 1patient achieved CR and 15 patients achieved PR. 11.8% achieved pathological complete response, and 17.6% had a chemotherapy response score (CRS) of 3. PFS or OS data are not mature by cut-off date. Safety and adverse event (AE) were analyzed after completion of neoadjuvant therapy. Treatment-related AEs (TRAEs) of any grade were evaluated for all study populations. TRAEs of any grade occurred in 13 (76.5%) patients. Grade ≥3 TRAEs occurred in 3 (17.6%) patients. The most common TRAEs were thyroid dysfunction (23.5%) and bone marrow suppression (17.6%). Grade ≥ 3 irAE (immune⁃mediated colitis) occurred in 1 (5.9%) patient. All of the TRAEs, including severe AEs, were manageable, with no new safety concerns in this study. Conclusions: This study showed promising activity with a durable clinical response, supporting the potential of NAC with bispecific antibody AK104 in advanced-stage ovarian cancer. Meanwhile, long-term efficacy evaluation still needs following up. Clinical trial information: NCT05430906 .
Enhanced anti-ovarian cancer efficacy with MSLN-chimeric antigen receptor T cells secreting anti-CD39 antibody.
Authors: Zhu Haiyan , Li Xiaopei , Deng Qi , Zhang Yuchen , Wang Huajing , He Xiaowen , Li Xian-Yang
Published: July 2024

e17553

Background: The effectiveness of chimeric antigen receptor (CAR) T cell therapy directed at mesothelin (MSLN) in solid tumors, such as ovarian cancer, is hindered by the immunosuppressive tumor microenvironment (TME), where adenosine plays a crucial role in impairing CAR-T cell function. Preclinical and clinical studies have demonstrated that targeting CD39, a pivotal enzyme catalyzing the conversion of extracellular ATP into adenosine, yields significant antitumor effects. Therefore, combining MSLN CAR-T with an anti-CD39 antibody emerges as a potential therapeutic strategy against cancer. Methods: We have previously designed OriA631, an antibody antagonist targeting CD39 in VHH format. Our preclinical investigation has highlighted the outstanding potential of OriA631, showcasing superior performance in binding affinity, effective inhibition of CD39 enzyme activity, and remarkable in vivo high anti-tumor efficacy. Subsequently, we undertook further engineering of MSLN CAR-T cells to secrete the VHH component of OriA631 (MSLN CAR-T-CD39-VHH) and systematically assessed its antitumor effects in NSG mice. Results: Our data reveals that MSLN CAR-T cells exhibit a significant upregulation of CD39 upon activation by ovarian cancer cells in both in vitro and in the tumor microenvironment (TME). To assess the combined effect of MSLN CAR-T with anti-CD39, B-NDG mice were subcutaneously inoculated with 3x10^6 ovarian cancer cells (SKOV3-MSLNhi-CD39hi). Subsequently, different T cells (1x10^7 cells/mouse) were injected when the tumor reached around 80 mm³, and the groups were divided into Mock T, MSLN CAR-T, MSLN CAR-T-CD39-VHH, and MSLN CAR-T in combination with locally injected CD39 Ab (OriA631). The data demonstrated that MSLN CAR-T inhibited tumor growth from approximately 1000mm³ (Mock T group) to 300mm³ at day 30 relative to T cell injection. Tumors in the MSLN CAR-T in combination with OriA631 group were around 100mm³, suggesting a significant combination anti-tumor efficacy of MSLN CAR-T in conjunction with CD39 targeting. Furthermore, MSLN CAR-T-CD39-VHH, where MSLN CAR-T cells secrete the VHH component of OriA631, completely eliminated the tumor at day 18 with no relapse during the experimental period. This result underscores the superior anti-tumor efficacy of MSLN CAR-T-CD39-VHH, with the high level of VHH component of CD39 Ab observed in the TME. Importantly, the low or undetectable level of VHH component of CD39 Ab in the serum also indicates the safety of the product. Conclusions: Our study introduces the innovative therapeutic agent MSLN CAR-T-CD39-VHH, showcasing superior anti-tumor efficacy and the potential for reduced antibody-associated side effects. These findings strongly endorse the application of MSLN CAR-T-CD39-VHH as a promising and impactful therapeutic approach for the treatment of ovarian cancer.
Prospective observational study of nutritional and immunological indices as predictive biomarkers of response to immune checkpoint inhibitors in non-small cell lung cancer (ICI-PREDICT study).
Authors: Takamori Shinkichi , Shimokawa Mototsugu , Yamaguchi Masafumi , Mori Masahide , Kuyama Shoichi , Oki Masahide , Nishimura Yoshifumi , Nakatomi Katsumi , Yanai Hidetoshi , Sukoh Noriaki , Hatakeyama Nobuo , Kita Toshiyuki , Fujiwara Keiichi , Chibana Kenji , Okamoto Masaki , Takenoyama Mitsuhiro
Published: July 2024

e20524

Background: Nutritional and immunological indices, including controlling nutritional status (CONUT) score, skeletal muscle area (SMA), and neutrophil-to-lymphocyte ratio (NLR) have been reported as predictors of response to immune checkpoint inhibitor (ICI) in non-small cell lung cancer (NSCLC). The aim of this prospective, multicenter study is to evaluate the clinical impact of pre- or early post-treatment changes in nutritional and immunological indices on treatment outcomes in patients with advanced NSCLC treated with first-line ICIs. Methods: We enrolled 301 advanced NSCLC patients treated with ICIs (monotherapy or combined with chemotherapy) as first-line therapy, without any oncogene mutations, and available data on programmed cell death-ligand 1 (PD-L1) expression (150 in training and 151 in validation cohorts) from March 2020 to November 2022. The CONUT score, SMA at the L3 level (cm2/m2), and NLR, were evaluated before treatment initiation and at the first response evaluation. Cut-off values were determined by receiver operating characteristic curves with objective response as the outcome in the training cohort. The primary endpoint was progression-free survival (PFS). For exploratory study, serum before treatment was collected to measure 15 muscle-derived cytokines (Apelin, BDNF, CX3CL1, EPO, FABP3, FSTL1, FGF21, IL-6, IL-15, Irisin, LIF, Musclin, Myostatin, OSM, and SPARC) (n = 123). Results: The median follow-up period and PFS was 17.5 (range: 7.3-39.4) and 6.9 (range: 0.1-31.5) months, respectively. In the training cohort, men (hazard ratio [HR]: 0.52, 95% confidence interval [CI]: 0.30-0.90, p = 0.0183), ΔCONUT < 0 (HR: 0.59, 95% CI: 0.35-0.98, p = 0.0431), and ΔSMA > −0.13 (HR: 0.56, 95% CI: 0.33-0.96, p = 0.0333) were independent predictors for PFS. In the validation cohort, PD-L1 ≥ 50% (HR: 0.54, 95% CI: 0.34-0.84, p = 0.0061), NLR < 3.65 (HR: 0.47, 95% CI: 0.30-0.74, p = 0.0011), and ΔSMA > −0.13 (HR: 0.61, 95% CI: 0.38-0.98, p = 0.0421) were independent predictors for PFS. In the exploratory study, multivariate analysis including muscle-derived cytokines (continuous variables) revealed that performance status = 0 (HR: 0.24, 95% CI: 0.12-0.48, p < 0.0001), without baseline prednisone (≥ 10 mg/day) (HR: 0.17, 95% CI: 0.05-0.58, p = 0.0213), smoking history (HR: 0.34, 95% CI: 0.14-0.81, p = 0.0269), and FSTL1 (HR: 0.97, 95% CI: 0.93-0.99, p = 0.0185) were independent predictors of PFS. Conclusions: ΔSMA was the only factor validated as an independent predictor of PFS. The underlying biological mechanisms may be related to skeletal muscle-derived FSTL1. Clinical trial information: UMIN000040450.
Exposure-response (ER) analyses of efficacy and safety of trastuzumab deruxtecan (T-DXd) to inform dosing recommendation in HER2-mutant non-small cell lung cancer (NSCLC).
Authors: Khatri Amit , Polhamus Daniel , Cobbina Enoch , Garcia Ramon , Yoder Todd , Abutarif Malaz , Garimella Tushar
Published: July 2024

e20545

Background: T-DXd, a novel human epidermal growth factor receptor 2 (HER2) targeting antibody drug conjugate, was evaluated at doses of 5.4 and 6.4 mg/kg every three weeks in Phase 1 or 2 trials in HER2 mutant (HER2m) NSCLC subjects, including Destiny-Lung01 (DL-01) and DL-02 trials1,2. ER analyses of key efficacy and safety endpoints were conducted to support the dosing recommendation of T-DXd in HER2m NSCLC. Methods: Exposure-efficacy (EE) analysis was performed using confirmed objective response (cORR) data from HER2m NSCLC in Phase 1-2 trials (N = 181). The dataset included primary analysis data cut from DL-011 and interim analysis data cut from DL-02. Exposure-safety (ES) analyses of T-DXd were performed, using pooled data from 11 Phase 1-3 trials (N = 1850) across tumor types, including DL-01 and DL-02, for safety endpoints of adverse events (AEs) associated with dose reduction or discontinuation, Grade3+ (G3+) AEs, serious AEs, G3+Anemia, G3+neutropenia, G3+thrombocytopenia, adjudicated any grade interstitial lung disease (ILD), and G3+ ILD. cORR and all safety endpoints, except ILD were analyzed by logistic regression; any grade ILD was analyzed by parametric time-to-event analysis. The T-DXd or DXd exposure metric and numerous patient-specific covariates were tested in the analysis. Results: T-DXd exposure had a positive but shallow relationship with cORR. The predicted cORR varied from 57% (95% credible interval (CrI): [36, 77]) to 65% (95% CrI: [41, 84]) across 5th and 95th percentile of T-DXd exposure respectively. No clinically meaningful difference in cORR was estimated across 5.4 and 6.4 mg/kg doses with predicted cORR values of 53% (95% CrI: [44, 60]) and 55% (95% CrI: [47, 62]) at T-DXd doses of 5.4 mg/kg and 6.4 mg/kg, respectively. ES relationships were consistent with previous T-DXd ES analyses in breast cancer (BC). Model-predicted AE rates were lower (up to 9%) in 5.4 mg/kg compared to the 6.4 mg/kg dose. Model-predicted safety at 5.4 mg/kg dose in HER2m NSCLC was similar to the approved dose of 5.4 mg/kg in BC. Conclusions: The ER analyses showed no clinically meaningful difference in efficacy between 5.4 and 6.4 mg/kg doses of T-DXd; and safety events were lower in 5.4 mg/kg, thus supporting the 5.4 mg/kg recommended dose for HER2m NSCLC. These findings were later confirmed based on primary analysis in DL-022 and support the utility of ER analyses in dosing recommendation. Reference: Li BT et al. N Engl J Med 2022;386:241-51 Goto K et al. J Clin Oncol 41:4852-4863. Clinical trial information: NCT03505710 , NCT04644237 .
Survival in de novo metastatic merkel cell carcinoma according to sites of metastases.
Authors: Khaddour Karam , Liu Mofei , Giobbie-Hurder Anita , Kim Emily , Thakuria Manisha , Silk Ann W.
Published: July 2024

e21511

Background: Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer with a propensity to form regional and distant metastases. Due to the low incidence of MCC, there is a dearth of studies evaluating the impact of the sites of metastases on clinical outcomes. Recently, we found that liver and bone metastases were associated with shorter overall survival (OS) in patients with recurrent metastatic MCC. Herein, we report on the prognostic impact associated with specific metastatic sites in patients who presented with de novo Stage IV MCC at Dana-Farber Cancer Institute. Methods: Patients were included if they consented to participate in a biobanking study (DF/HCC #09-156) and presented with one or more distant sites of metastases on imaging at the time of diagnosis due to MCC. The following data were collected: age at diagnosis, gender, race, metastatic site(s) at the time of diagnosis, date of diagnosis, first-line treatment, treatment type, best response on imaging, progression, and vital status. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method. Fisher’s exact test was used for response rate analysis. Results were considered statically significant if p < 0.05. Results: 34 participants presented with one or more distant metastatic sites of MCC between the years 2010 and 2022. There was no association between the number of metastatic sites at presentation and OS (p= 0.58), PFS (p= 0.79), or response rates (p= 0.53). Among the organ sites we examined, bone metastases were associated with shorter OS (8.2 versus 25.2 months, HR = 2.4; 95% CI 1.01 – 5.7, p= 0.04). There were non-significant associations between OS and metastases in lymph nodes (p= 0.07) and in liver (p= 0.16). The location of metastases was not associated with the response rate to first-line treatment. There was no statistically significant association between any site of metastases and PFS. Conclusions: In this cohort of patients with de novo metastatic MCC, the presence of bone metastases, but not the number of overall organs involved, was associated with significantly worse overall survival. If bone involvement is confirmed to be a negative prognostic factor in an independent dataset, it would warrant mechanistic studies to further our understanding of this interplay and a re-examination of the AJCC staging for metastatic disease.
Spatially mapping the single-cell immune landscapes of melanoma brain metastases using imaging mass cytometry.
Authors: Magrill Jamie , Allard-Puscas Sarah , Gu Claris , Ramsay LeeAnn , Lajoie Mathieu , Karimi Elham , Maritan Sarah M , Dankner Matthew , Rezanejad Morteza , Zuo Dongmei , Wei Yuhong , Petrecca Kevin , Guiot Marie-christine , Routy Bertrand , Siegel Peter M , Quail Daniela , Walsh Logan , Mihalcioiu Catalin Liviu Dragos , Stagg John , Watson Ian
Published: July 2024

e21517

Background: Up to 60% of metastatic melanoma patients develop brain metastases, and 5% develop leptomeningeal disease (LD), which presents with the worst prognosis of any melanoma brain metastasis (MBM) infiltration pattern. Median survival duration for MBM is ~12 months, however for LD patients it can be < 10 weeks. The spatial immune landscape of MBM with and without LD remains poorly understood. Methods: To spatially characterize the tumor microenvironment (TME) of MBM, we performed CyTOF Imaging Mass Cytometry (CyTOF-IMC) on a highly multiplexed panel of 35 antibodies for 21 MBMs (13 with LD, 8 without LD). We performed a novel cell segmentation, cell type assignment and identification approach to identify cell lineages to spatially characterize the TME of MBMs, segmenting and classifying 130,000 cells into 19 cell types. Results: We found enrichment of dendritic cells in the direct neighbourhood of melanoma cells of patients with LD (p = 0.019) and trends towards elevation of anti-tumoral monocyte populations in the TME of patients without LD. To investigate survival outcomes, we divided our cohort into long (≥365days) and short-survivors ( < 365 days), and found significant elevation of anti-tumoral T-cell populations (Total T-cells, CD8+ T-cells, CD4+ T-cells and CD3+CD4-CD8- T-cells, p < 0.05), and closer proximity of T-cells (CD8+ & CD4+ T-cells) to melanoma cells (p < 0.05). Survival analysis using median cell-proportion for each T-cell subset showed statistically significant (p < 0.05) survival differences between patients with high and low cell-proportions of CD8+ T-cells and CD4+ T-cells, with similar trends observed for a subset of patients (n = 13) with LD and a subset of patients treated with ICIs (n = 10), and results were confirmed by a Cox Regression Model. Cellular neighborhood (CN) analysis was performed generating N = 12 stable CNs. We found patients with higher proportions of CN9 (M1-like-microglia/M2-like-microglia/melanoma), CN10 (M1-like-macrophages/M2-like-macrophages/melanoma) and CN12 (Cytotoxic-T-cells/Helper-T-cells/melanoma) was associated with longer overall survival after diagnosis with MBM (p < 0.01). Conclusions: Proportion and proximity of anti-tumoral monocyte and T-cell populations may play a key role in modulating tumor response and overall survival for patients with MBM, including for patients with LD or for patients treated with ICIs.