Treatment Of Carcinoma Research Articles

Abstract ED02-03: Innovative approaches at the diagnosis and treatment of invasive lobular carcinoma

Abstract Invasive Lobular Carcinoma (ILC) represents a unique subtype of breast cancer characterized by distinctive clinical and molecular features. This presentation aims to delve into innovative approaches in the diagnosis and treatment of ILC, focusing on novel techniques in imaging, unique molecular findings, signaling pathway alterations, targetable biomarkers, and microenvironment profiling that can pave the way for the development of novel therapies. Imaging Techniques in ILC: Accurate diagnosis is the foundation for effective treatment. ILC often presents diagnostic challenges due to the fact that lobular cells tends to infiltrate the affected organs in a diffuse manner instead of forming a discrete tumor mass making diagnostic imaging such as screening mammograms and CT scans less precise. This presentation will explore cutting-edge imaging techniques such as contrast-enhanced mammography, novel radioisotopes for positron emission tomography (PET) such as Fluoroestradiol F18 (FES), Fluciclovine and prostate-specific membrane antigen (PSMA) for improved detection and characterization of ILC lesions. Furthermore, we will discuss emerging modalities like radiomics and artificial intelligence, which hold promise in enhancing early diagnosis and risk assessment. Molecular Insights into ILC: ILC is distinguished by its unique molecular profile, notably the loss of E-cadherin expression. We will delve into recent advancements in understanding the molecular landscape of ILC, including genomic alterations, epigenetic changes, and the role of signaling pathways providing insights into potential therapeutic vulnerabilities. Targetable Biomarkers and Pathways: Identification of targetable biomarkers is essential for the development of precision therapies in ILC. This presentation will highlight promising targets, including ERBB2 (HER2), ROS1, TROP2, AKT1 along with other novel biomarkers. Microenvironment Profiling: The tumor microenvironment plays a pivotal role in cancer progression and therapy response. We will discuss recent advancements in characterizing the ILC microenvironment, including the immune cell infiltrate and stromal components. Understanding the dynamic interplay between the tumor and its microenvironment can inform the development of immunotherapies and combination strategies tailored to ILC. In conclusion, this presentation will provide a comprehensive overview of the latest innovations in ILC diagnosis and treatment. Our exploration of advanced imaging techniques, molecular findings, targetable pathways, biomarkers, and microenvironment profiling will shed light on the exciting potential for personalized therapeutic approaches in the management of ILC. By staying at the forefront of these developments, we can pave the way for improved outcomes and enhanced quality of life for patients with ILC. Citation Format: J. Mouabbi. Innovative approaches at the diagnosis and treatment of invasive lobular carcinoma [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr ED02-03.

Abstract PO5-16-11: Novel antibody-drug-conjugates in clinical routine: adherence, efficacy and tolerability - real-world data from German breast centers

Abstract The third-generation antibody-drug conjugates, Trastuzumab-Deruxtecan (T-DXd) and Sacituzumab Govitecan (SG), have been approved for the treatment of metastatic breast carcinoma in various subtypes and therapeutic settings based on compelling Phase III study data. (DESTINY-Breast03 (T-DXd; HER2-positive), DESTINY-Breast04 (T-DXd; HER2-low), ASCENT (SG; triple-negative), and TROPiCS-02 (SG; HR+/HER2-negative). The aim of this retrospective study conducted at two major German Breast centers was to evaluate the tolerability, adherence, and efficacy of both substances in the real-world setting. All patients treated outside of clinical trials with T-DXd or SG at the Department of Gynecology and Obstetrics, Ulm University Hospital and the Department of Women’s Health, Tuebingen University Hospital between November 2020 and May 2023 were included in this retrospective analysis. Seventy-five patients were included [T-DXd: 46; SG: 29]. The mean duration of therapy was 5.4 months [T-DXd: 6.2; SG: 4.2]. The real-world cohort was more heavily pretreated than the corresponding study cohorts, with a mean of 4.2 systemic therapies in the metastatic setting prior to T-DXd therapy and 3.6 systemic therapies prior to SG therapy. The administered cumulative dose on average was 87.9% [T-DXd: 94%; SG: 79%] of the theoretical full dose or 95.3% [T-DXd: 98%; SG: 92%] when considering dose reductions that occurred. Hematotoxicities of CTC ≥ 3° occurred in 11% of patients treated with T-DXd and in 41% of patients treated with SG. Neutropenia was the predominant severe hematotoxicity (CTC≥III°) observed during SG therapy, occurring in 38% of patients. The occurrence of neutropenia during SG therapy was reduced with primary prophylactic administration of Granulocyte-Colony Stimulating Factor (GCSF), with a rate of 29% (21/29) of patients experiencing neutropenia ≥CTC-III°, compared to 63% (8/29) without primary prophylactic GCSF. Therapy-associated pneumonitis under T-DXd occurred in 5 out of the 46 included patients and was successfully treated with corticosteroids in all cases (CTC II° in 4 cases, CTC III° in 1 case). The median progression-free survival (PFS) from initial administration was 7.7 months under T-DXd [HER2-positive: 9.0; HER2-low: 6.1], and 4.8 months under SG [TNBC 4.8; HR+/HER2-negative: 2.8]. The median overall survival from initial administration was 27.1 months under T-DXd [HER2-positive: 27.1; HER2-low: not reached], and 11.9 months under SG therapy [TNBC: 11.0, HR+/HER2-negative: not reached]. This analysis provides evidence of the efficacy and tolerability of T-DXd and SG in a heterogeneous and heavily pretreated cohort in a real-world setting. However, a conclusive assessment of progression-free survival (PFS) and overall survival (OS) is not feasible yet, as a substantial number of patients are still under treatment. Updated PFS and OS data, with a specific focus on the therapy indication, will be presented at the meeting. Citation Format: Henning Schäffler, Dominik Dannehl, Kristina Veselinovic, Franziska Mergel, Kerstin Pfister, Brigitte Rack, Visnja Fink, Elena Leinert, Lea Volmer, Tobias Engler, Sara Brucker, Wolfgang Janni, Andreas Hartkopf. Novel antibody-drug-conjugates in clinical routine: adherence, efficacy and tolerability - real-world data from German breast centers [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-16-11.

Wound-Healing Effects of Common Antineoplastic Agents and Perioperative Considerations for the Orthopaedic Surgeon.

In oncologic patients, optimal postoperative wound healing is crucial for the maintenance of systemic therapies and improved survival. Although several risk factors for postoperative wound complications have been identified, the clinical effect of new antineoplastic agents on wound healing remains uncertain. The available literature on the effect of antineoplastic agents in wound healing is complex to analyze because of other confounding risk factors such as radiation therapy and certain patient-specific variables. Available perioperative drug recommendations are based on database opinion and case reports from adverse event alerts. This review highlights the characteristics of old and new antineoplastic agents commonly used in the treatment of sarcoma, carcinoma, and other cancers and their potential effects on the wound-healing process. It also aims to provide perioperative treatment cessation recommendations to guide orthopaedic surgeons and prevent drug-related wound complications to the fullest extent possible.

Abstract PO5-20-09: LOCOREGIONAL MANAGEMENT OF DE NOVO STAGE IV HORMONE-POSITIVE BREAST CARCINOMA AFTER CDK 4/6 INHIBITOR TREATMENT

Abstract Systemic therapy remains the backbone for treatment of metastatic breast carcinoma. Locoregional treatment of the primary tumor remains controversial. While it has an established role in the palliative setting, its survival benefit remains unclear. The rationale behind locoregional approach is the reduction of tumor burden and the removal of cancer stem cells which may propagate the disease. In previous literature, hormone-positive breast cancer seems to be the best candidate for locoregional treatment in the presence of synchronous metastases. We present a case of a 43 year-old, female, with no known comorbidities, who sought consult due to note of a hard lump on her right breast. Core needle biopsy of the right breast mass was performed which showed invasive breast carcinoma, no special type, Nottingham histologic grade 2. On immunohistochemistry, tumor was ER +8, PR +8, Ki 67 90%, Her-2 neu negative. Baseline positron emission tomography/CT (PET/CT) scan showed hypermetabolic, heterogeneously-enhancing lobulated right breast mass, 3 × 6.7 × 7.7 cm, with smaller hypermetabolic adjacent nodules. There was also note of multiple enhancing, hypermetabolic lung and pleural nodules, and lymphadenopathies in the mediastinal, right axillary, right cardiophrenic and perigastric areas. Well-defined, hypermetabolic heterogeneously hypoenhancing masses were also seen in segments II and VII of the liver. There was also note of right-sided pleural effusion. Ultrasound-guided thoracentesis was done which turned positive for malignant cells on pleural fluid analysis. She underwent 4 cycles of chemotherapy with Doxorubicin and Paclitaxel. Reevaluation PET-CT scan revealed partial response. Patient was then started on Ribociclib plus Letrozole with ovarian function suppression for 18 months. On latest reevaluation PET/CT scan, there was no evidence of hypermetabolic metastatic disease, with demonstration of hypermetabolic activity only in the right breast. The patient then underwent right total mastectomy, with histopathologic findings of residual invasive carcinoma, Nottingham histologic grade 3, residual tumor size of 3.5 cm, with 95% tumor cellularity and lymphovascular invasion identified, ypT2. All surgical margins were negative for tumor. Currently, the patient has no evidence of disease, with ribociclib and letrozole continued until disease progression or unacceptable toxicity. In this case, surgery of the primary tumor was performed in the presence of a responsive metastatic disease, with the primary tumor being the only evidence of disease. With the advent of newer therapy options like cyclin-dependent kinase 4/6 inhibitors offering outstanding survival benefit for metastatic disease, a more aggressive and synergistic approach with locoregional therapy may be done to eradicate the tumor burden, translating to better long-term survival. Locoregional management of the primary tumor should be discussed in the context of a multidisciplinary team approach and should be individualized based on the individual patient’s need. Citation Format: Raye Angeli Abella, Rubi Li. LOCOREGIONAL MANAGEMENT OF DE NOVO STAGE IV HORMONE-POSITIVE BREAST CARCINOMA AFTER CDK 4/6 INHIBITOR TREATMENT [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-20-09.

An investigation of the advantages of the adjustable angle stitch template compared with CT-guided 125I seeds free-hand implantation in the treatment of non-small cell lung carcinoma

Objective: To investigate the advantages of adjustable angle needle path template compared with CT-guided 125I seeds free-hand implantation in the treatment of non-small cell lung carcinoma. Methods: This randomized controlled trial involved the retrospective analysis of the clinical data of 45 patients with non-small cell lung carcinoma who underwent 125I seeds implantation at the Shandong Cancer Hospital, Shaanxi Provincial Tumor Hospital and The Third Affiliated Hospital of Shandong First Medical University from May 2018 to January 2023. Patients were divided into the template (n=21) and free-hand (n=24) groups, according to the modality used. The template group comprised 16 males and 5 females, aged (66±12) years, while the free-hand group comprised 16 males and 8 females, aged (62±8) years. The dose distribution, implant quality, intraoperative computed tomography (CT) scan times, and 125I seed reseeding numbers after implantation were compared between the two groups to evaluate the potential advantages of adjustable angle needle path template-assisted implantation over free-hand 125I implantation. Results: Statistical comparison revealed no significant differences in age (t=1.16, P=0.253), tumor volume [(71±26) vs. (71±22) cm3, t=0.21, P=0.837), or any other baseline characteristics between the template and free-hand groups. Overall, 45 patients successfully completed the operation. In the template group, the mean values of the D90 (dose that was delivered to 90% of the target volume), V100 (the target volume receiving 100% of the prescription dose), coverage index (CI), relative dose homogeneity index (HI), and external volume index (EI) pre-and post-implantation were (131.0±2.1) vs. (131.1±5.5) Gy, 90.0%±0.4% vs. 91.0%±2.8%, 0.83±0.07 vs. 0.82±0.05, 41%±11% vs. 37%± 13%, and 4.3%(2.9%, 14.0%) vs.8.8%(5.2%,14.6%), respectively. None of these parameters showed any significant difference (all P>0.05). In the free-hand group, the mean value of D90 pre- and post-implantation was (131.4±2.9) vs.(128.6±8.6) Gy, showing no significant difference (P>0.05), the mean values of V100, CI, HI, and EI pre-and post-implantation were 90.0%±0.5% vs. 89.0%± 3.0%, 0.84±0.04 vs. 0.71±0.09, 41%±9% vs. 34%±10%, and 7.7% (4.9%,11.0%) vs.24.2% (14.3%, 35.3%), respectively, showing significant differences (all P<0.05). The number of reseeding seeds in the template group was lower than that in the free-hand group [2.0 (0,2.5) vs. 4.0 (2.0, 7.0), Z=-3.36, P=0.001], showing a statistically significant difference. Further, the number of CT scans in the template group was significantly less than that in the free-hand group (3.9±0.5 vs. 4.6±1.2, t=-2.54, P=0.016). The incidences of adverse reactions were 23.8% (5/21) and 33.3% (8/24) (χ2=12.86, P=0.002) in the template and free-hand groups, respectively, indicating a significant difference. Conclusion: Compared with free-hand implantation, use of the adjustable angle needle path template technique can shorten the operation time, reduce the number of scans, reduce the incidence of complications, and improve treatment efficacy to a certain extent.

Tivozanib-induced activation of the mitochondrial apoptotic pathway and suppression of epithelial-to-mesenchymal transition in oral squamous cell carcinoma.

The potential of tivozanib as a treatment for oral squamous cell carcinoma (OSCC) was explored in this study. We investigated the effects of tivozanib on OSCC using the Ca9-22 and CAL27 cell lines. OSCC is a highly prevalent cancer type with a significant risk of lymphatic metastasis and recurrence, which necessitates the development of innovative treatment approaches. Tivozanib, a vascular endothelial growth factor receptor inhibitor, has shown efficacy in inhibiting neovascularization in various cancer types but has not been thoroughly studied in OSCC. Our comprehensive assessment revealed that tivozanib effectively inhibited OSCC cells. This was accompanied by the suppression of Bcl-2, a reduction in matrix metalloproteinase levels, and the induction of intrinsic pathway-mediated apoptosis. Furthermore, tivozanib contributed to epithelial-to-mesenchymal transition (EMT) inhibition by increasing E-cadherin levels while decreasing N-cadherin levels. These findings highlight the substantial anticancer potential of tivozanib in OSCC and thus its promise as a therapeutic option. Beyond reducing cell viability and inducing apoptosis, the capacity of tivozanib to inhibit EMT and modulate key proteins presents the possibility of a paradigm shift in OSCC treatment.

Network Pharmacological Analysis and Experimental Validation of the Effects of Silybin on Proliferation, Migration, and Immunotherapy of Papillary Thyroid Cancer.

The study aimed to use network pharmacology research and in vitro experiments to investigate the material basis and molecular mechanisms of silybin in the treatment of papillary thyroid carcinoma. Papillary thyroid cancer (PTC) has a decent prognosis; however, recurrence and metastasis are the leading causes of death in patients with PTC. A key research focus in thyroid cancer treatment is the inhibition of PTC proliferation, invasion, and migration. Silybin, the major active element in the traditional Chinese herb silymarin, has been used to treat a range of diseases, including cancer, but no study has been undertaken to determine whether it can help prevent PTC. In this study, we attempted to determine through network pharmacology and in vitro experiments if silybin inhibits the development of papillary thyroid cancer by inhibiting cell cycle and invasive migration. To predict the probable targets and underlying mechanisms of silybin against PTC, a network pharmacology research was performed. In vitro experiments were conducted to further evaluate silybin's anti-cancer properties and priority targets against PTC. The datasets revealed a total of 489 silybin targets acting on PTC, and functional enrichment analysis suggested that the target genes were enriched in functions and pathways related to PTC development, invasion, migration, and immunotherapy. By constructing these target PPI networks, the seven hub genes, fibronectin 1 (FN1), tissue inhibitor of metalloproteinases 1 (TIMP1), N-cadherin (CDH2), collagen type III alpha 1 chain (COL3A1), cyclin D1 (CCND1), AP-1 transcription factor subunit (JUN), and hepatocyte growth factor receptor (MET) were found. These hub genes were determined to be highly linked to a worse clinicopathological form, a higher risk of metastatic recurrence, and a worse prognosis of PTC. The common immunological checkpoint gene expression levels were positively correlated with the expression levels of the hub genes. Silybin decreased the proliferative and metastatic capacity of PTC cells, according to in vitro investigations. When PTC was treated with silybin, the FN1/AKT signaling pathway was blocked, CCND1 expression was reduced, and CDH2, Vimentin, Snail, Slug and PD-L1 expressions were dramatically reduced, while E-cadherin expression was significantly elevated. These findings provide preliminary evidence that silybin inhibits PTC cell proliferation, metastasis, and invasion by altering the FN1/AKT signaling pathway and inhibiting the EMT process. Silybin can reverse immunosuppression in papillary thyroid cancer by affecting immunological checkpoint gene expression levels. These studies provide a theoretical and experimental scientific basis for the potential anticancer effects of silybin on PTC.

Elective Irradiation of Retropharyngeal Lymph Nodes as an Indication for Adjuvant Radiotherapy Following Trans Oral Surgery for Tonsil Cancer: Elective Irradiation of the Retropharyngeal Space

Treatment of squamous cell carcinoma of the tonsil involves primary radiotherapy (RT) or surgical resection. Historically, if radiotherapy was the primary or adjuvant treatment modality, most of the bilateral retropharyngeal lymph nodes (RPLN) were treated electively with a therapeutic dose for subclinical disease, regardless of if radiographically pathologic lymph nodes were seen on initial diagnostic imaging. De-escalation strategies include the incorporation of transoral surgery (TOS) with the goal to either eliminate or reduce the dose of adjuvant RT or chemotherapy. TOS does not include elective removal of the RPLNs and no guideline or outcome paper recommends adjuvant RT specifically to electively treat RPLNs. In this topic discussion, we discuss pertinent literature and suggest management decisions. The management decisions discussed in this topic discussion pertain only to tonsillar primaries and not those of the soft palate or base of tongue.

Regorafenib with immunotherapy versus regorafenib alone as second-line treatment for hepatocellular carcinoma: A multicenter real-world study.

Regorafenib remains the standard and widely used second-line strategy for advanced hepatocellular carcinoma (HCC). There is still a lack of large-scale multicenter real-world evidence concerning the concurrent use of regorafenib with immune checkpoint inhibitors (ICI). This study aims to evaluate whether combining regorafenib with ICI provides greater clinical benefit than regorafenib monotherapy as second-line therapy for advanced HCC under real-world circumstances. The study included 208 patients from five medical facilities. One hundred forty-three patients received regorafenib plus ICI combination therapy, while 65 patients received regorafenib monotherapy. Propensity score matching (PSM) analysis was employed. The regorafenib plus ICI group demonstrated significantly higher objective response rate (24.3% vs. 10.3%, after PSM, p = 0.030) and disease control rate (79.4% vs. 50.0%, after PSM, p < 0.001) compared to the regorafenib monotherapy group based on mRECIST criteria. Median progression-free survival (7.9 vs. 3.2 months, after PSM, p < 0.001) and overall survival (25.6 vs. 16.4 months, p = 0.010, after PSM) were also considerably longer in the regorafenib plus ICI group. The incidence of Grades 3-4 treatment-related adverse events (TRAEs) was marginally greater in the regorafenib plus ICI group than in the regorafenib group (23.8% vs. 20.0%, p = 0.546). Notably, there were no instances of treatment-related mortality or emergence of new TRAEs in any treatment group. The combination of regorafenib and ICI shows potential as a viable second-line treatment for advanced HCC, exhibiting favorable efficacy while maintaining a tolerable safety profile in contrast to regorafenib monotherapy.

Camrelizumab, chemotherapy and apatinib in the neoadjuvant treatment of resectable oesophageal squamous cell carcinoma: a single-arm phase 2 trial

In resectable oesophageal squamous cell carcinoma (ESCC), the efficacy of camrelizumab combined with chemotherapy and apatinib followed by minimally invasive oesophagectomy is not clear. We aimed to fill this knowledge gap. This investigator-initiated, single-arm, prospective, phase 2 trial was performed at the Second Affiliated Hospital of Zhejiang University, China. Patients (aged 18-75 years) who were histologically or cytologically diagnosed with ESCC were deemed suitable to participate in this trial. Patients received 2-3 cycles of neoadjuvant therapy with camrelizumab, nedaplatin, albumin paclitaxel, and apatinib; each cycle was repeated every 14 days. Surgery occurred 4-6 weeks after the last neoadjuvant treatment cycle. The primary outcome was the pathological complete response (PCR) rate of the tumour and lymph nodes. The changes in the peripheral blood immunoprofile among patients without PCR (ie, non-PCR [NPCR]) and with PCR were assessed by mass cytometry. This study was registered with ClinicalTrials.gov, NCT04666090. 42 patients were enrolled between November 23, 2020 and December 31, 2022. The disease control rate was 100.0% (95% CI, 91.6-100%), and the objective response rate was 83.3% (95% CI, 68.6-93.0%). Six (14.3%) patients experienced grade 3 adverse events. The most common were white blood cell count decrease (31.0%), alopecia (81.0%), asthenia (38.1%), and reactive cutaneous capillary endothelial proliferation (35.7%). 41 patients received minimally invasive oesophagectomy; all 41patients achieved R0 resection, and 18 (43.9%, 95% CI, 28.5-60.3%) patients achieved PCR. The median follow-up was 23 months and the 2-year survival rate was 85.9%. T-cell subsets in both the PCR and NPCR groups exhibited consistency in response to neoadjuvant therapy. In contrast, some of natural killer (NK) cells (NK-C03, NK-C11), B cells (B-C06) and monocytes (M-C05), exhibited significant differences between the PCR and NPCR groups before neoadjuvant therapy. M-C06 had a significant difference in the PCR group and NPCR group after neoadjuvant therapy. NK-C12 and B-C15 showed significant differences both before and after neoadjuvant therapy. The application of camrelizumab, chemotherapy and apatinib in the neoadjuvant setting for locally advanced ESCC has shown promising antitumour activity and an acceptable safety profile in this single-arm study. In the neoadjuvant setting, NK cell, B cell, and monocyte subsets exhibited greater predictive power for immunotherapy responsiveness than T-cell subsets. Longer follow-up to assess survival outcomes and a phase 3 randomised trial are needed to further evaluate the proposed treatment. The China Anti-Cancer Association and the "Leading Goose" Research and Development Project of Zhejiang Province.

Efficacy of Lenvatinib Combined with PD-1 Inhibitor versus Sorafenib and PD-1 Inhibitor with or Without TACE for Hepatocellular Carcinoma with Extrahepatic Metastasis.

Lenvatinib or Sorafenib combined with programmed cell death protein-1 (PD-1) inhibitor as recommend treatment of advanced hepatocellular carcinoma (HCC) with extrahepatic metastasis (EHM). We aimed to compared the prognosis of Lenvatinib plus PD-1 inhibitor (Len+PD-1) versus Sorafenib plus PD-1 (Sora+PD-1) as an initial therapy for HCC with EHM. Incorporating a sum of 229 HCC patients with EHM were encompassed within this study, with 127 in the Sora+PD-1 group and 102 in the Len+PD-1 group. Through propensity score matching (PSM), we compared overall survival (OS), progression-free survival (PFS), and patient safety between these two groups. The median OS were 13.0 months and 14.2 months in the Sora+PD-1 group and Len+PD-1 group. The 6-, 12-, and 24-month OS rates were 92.9%, 58.9% and 5.6% in Sora+PD-1 group and 93.1%, 61.8% and 22.6% in Len+PD-1 group, respectively. The Len+PD-1 group had obviously better OS than the Sora+PD-1 group (P = 0.002). The 3-, 6-, and 12-month PFS rates were 76.4%, 27.6% and 1.6% in Sora+PD-1 group and 86.2%, 50.5% and 12.2% in Len+PD-1 group, respectively. Compared with Sora+PD-1 group, the Len+PD-1 group had obviously better PFS (P < 0.001). Analysis within subgroups showed that OS was significant in patients receiving TACE in Len+PD-1 group than Sora+PD-1 group (p = 0.003). Len+PD-1 group had longer OS and PFS than Sora+PD-1 group for patient with EHM. In addition, OS in patients received TACE was improved with Len+PD-1 treatment. For patients without TACE, there was no significance between Sora+PD-1 and Len+PD-1 groups.

Chemotherapy, immunotherapy, or combination first-line treatment for metastatic urothelial carcinoma of the bladder: A large real-world experience

IntroductionFirst-line systemic therapy for metastatic urothelial carcinoma of the bladder (mUC) consists of platinum-based chemotherapy in most patients and PD1/L1 inhibitors in selected patients. Multiple combination chemoimmunotherapy trials failed to show a clear benefit over chemotherapy alone. We used real-world data to evaluate clinical and sociodemographic factors associated with receipt of first-line chemotherapy, immunotherapy, or combination chemoimmunotherapy treatment for metastatic bladder cancer and examined differences in overall survival (OS). Materials and MethodsWe used the National Cancer Database to identify patients with stage IV mUC diagnosed between 2014 and 2018, who were treated with first-line immunotherapy, chemotherapy, or combination treatment. We performed multivariable logistic regression modeling to determine factors associated with treatment receipt Adjusted Kaplan-Meier survival analysis and multivariable Cox proportional hazards regression were used to evaluate the association between treatment and OS. ResultsIn our cohort of 4,169 patients, multivariable analysis identified increasing age (RRR: 1.07, 95%CI, 1.06–1.08) and comorbidity burden (, as independent predictors of receiving immunotherapy. Treatment at an academic facility was associated with increased likelihood of combination treatment (RRR: 1.29, 95%CI, 1.01–1.65). After IPTW, we found that combination therapy (hazard ratio [HR]: 0.72; 95%CI, 0.62–0.83) was associated with improved survival compared to chemotherapy. ConclusionsPatients with older age and more comorbidities were more likely to receive immunotherapy than chemotherapy for first-line treatment of metastatic urothelial carcinoma of the bladder. Utilization of chemoimmunotherapy was observed to be higher in academic centers and was associated with improved survival compared to chemotherapy.

Dabrafenib Alleviates Hepatotoxicity Caused by Lenvatinib via Inhibiting the Death Receptor Signaling Pathway

Lenvatinib is a multi-target inhibitor that exerts anti-tumor effects by inhibiting angiogenesis and is now commonly used as a first-line treatment for hepatocellular carcinoma. However, with the widespread use of lenvatinib, the problem of serious and fatal hepatotoxicity has become increasingly prominent. Currently, the mechanism behind this toxicity is not yet understood, and as a result, there is a lack of safe and effective intervention strategies with minimal side effects. Here, we established the model of lenvatinib-induced liver injury in vivo and in vitro and found that lenvatinib caused hepatotoxicity by inducing apoptosis. Further mechanistic studies in cellular models revealed that lenvatinib upregulated death receptor signaling pathway, which activated the downstream effector Caspase-8, and ultimately led to apoptosis. Meanwhile, lenvatinib-induced apoptosis was associated with ROS generation and DNA damage. In addition, after screening marketed drugs and natural products in combination with cellular modeling, we identified a potential co-administered drug, dabrafenib, which could alleviate lenvatinib-induced hepatotoxicity. Further mechanistic studies revealed that dabrafenib attenuated lenvatinib-induced hepatotoxicity by inhibiting the activation of the death receptor signaling pathway. Subsequently, cancer cell proliferation assays confirmed that dabrafenib did not antagonize the antitumor effects of lenvatinib. In conclusion, our results validate that apoptosis caused by the death receptor signaling pathway is the key cause of lenvatinib-induced hepatotoxicity, and dabrafenib alleviates lenvatinib-induced hepatotoxicity by inhibiting this pathway.

High incidence of lung cancer death after curative endoscopic submucosal dissection for superficial esophageal squamous cell carcinoma.

Following treatment of superficial esophageal squamous cell carcinoma (ESCC), surveillance for a second primary malignancy (SPM) is necessary. However, detailed evidence regarding the timing and prognosis of SPMs is insufficient. We aimed to clarify the details of SPMs and their effects on patient outcomes. This retrospective, multicenter study involved 11 hospitals. Patients with superficial ESCC curatively resected using endoscopic submucosal dissection between May 2005 and December 2012, were included in this study. The 5-year survival rate of 187 patients was 92.6% during a median follow-up duration of 96.8 months. Thirty-one patients died, 14 of whom died of SPMs. Compared to patients with SPMs detectable by esophagogastroduodenoscopy (EGD), patients with SPMs detectable only by modalities other than EGD had a significantly higher mortality rate (p < 0.001). Patients with second primary lung cancer (LC) had a high mortality rate (56.3%). Univariate and multivariate analyses showed that multiple Lugol-voiding lesions (LVLs) tended to be associated with SPMs (p = 0.077, hazard ratio [HR] 4.43, 95% confidence interval [CI]: 0.91-6.50), and metachronous ESCC was an independent risk factor for the incidence of second primary LC (p = 0.037, HR 3.51, 95% CI: 1.08-11.41). SPMs that cannot be detected by EGD, such as LC, must be considered after the curative resection of ESCC. We suggest strict screening by both EGD and computed tomography for patients with multiple LVLs or metachronous ESCC to detect SPMs in their early stages.

Efficacy and Safety of Radiation Segmentectomy with 90Y Resin Microspheres for Hepatocellular Carcinoma.

Background Limited data are available on radiation segmentectomy (RS) for treatment of hepatocellular carcinoma (HCC) using yttrium 90 (90Y) resin microsphere doses determined by using a single-compartment medical internal radiation dosimetry (MIRD) model. Purpose To evaluate the efficacy and safety of RS treatment of HCC with 90Y resin microspheres using a single-compartment MIRD model and correlate posttreatment dose with outcomes. Materials and Methods This retrospective single-center study included adult patients with HCC who underwent RS with 90Y resin microspheres between July 2014 and December 2022. Posttreatment PET/CT and dosimetry were performed. Adverse events were assessed using the Common Terminology Criteria for Adverse Events, version 5.0. Per-lesion and overall response rates (ie, complete response [CR], objective response, disease control, and duration of response) were assessed at imaging using the Modified Response Evaluation Criteria in Solid Tumors, and overall survival (OS) was assessed using Kaplan-Meier analysis. Results Among 67 patients (median age, 69 years [IQR, 63-78 years]; 54 male patients) with HCC, median tumor absorbed dose was 232 Gy (IQR, 163-405 Gy). At 3 months, per-lesion and overall (per-patient) CR was achieved in 47 (70%) and 41 (61%) of 67 patients, respectively. At 6 months (n = 46), per-lesion rates of objective response and disease control were both 94%, and per-patient rates were both 78%. A total of 88% (95% CI: 79 99) and 72% (95% CI: 58, 90) of patients had a per-lesion and overall duration of response of 1 year or greater. At 1 month, a grade 3 clinical adverse event (abdominal pain) occurred in one of 67 (1.5%) patients. Median posttreatment OS was 26 months (95% CI: 20, not reached). Disease progression at 2 years was lower in the group that received 300 Gy or more than in the group that received less than 300 Gy (17% vs 61%; P = .047), with no local progression in the former group through the end of follow-up. Conclusion Among patients with HCC who underwent RS with 90Y resin microspheres, 88% and 72% achieved a per-lesion and overall duration of response of 1 year or greater, respectively, with one grade 3 adverse event. In patients whose tumors received 300 Gy or more according to posttreatment dosimetry, a disease progression benefit was noted. © RSNA, 2024 Supplemental material is available for this article.

3-Epi-betulinic acid 3-O-β-D-glucopyranoside (eBAG) induces autophagy by activation of AMP-activated protein kinase in hepatocellular carcinoma

3-Epi-betulinic acid 3-O-β-D-glucopyranoside (eBAG) is a pentacyclic triterpene mainly distributed in food and medicinal plants, which exhibits various pharmacological properties. However, whether these functions are attributed to eBAG or additional components in these plants remain unknown. Herein, we report that eBAG exerted an inhibitory activity against hepatocellular carcinoma and esophageal cancer cells. EBAG induced non-apoptotic cell death in hepatocellular carcinoma cells. The eBAG-induced cell death was inhibited by knock-down of autophagy related gene (ATG) 5 and ATG7, by administration of 3-methyladenine, a selective autophagy inhibitor that suppresses phosphoinositide 3-kinase (PI3K), and by chloroquine, a classic autophagy flux inhibitor. We demonstrated that eBAG induced an autophagy-mediated cell death. Application of eBAG mimicked cellular bioenergetics depletion leading to the reduction of intracellular ATP, activation of AMP-activated protein kinase (AMPK), and inhibition of mTOR. Co-treatment with compound C, an AMPK inhibitor, abrogated cell death induced by eBAG. We further validated the anti-tumor effect of eBAG in the murine xenograft model of hepatocellular carcinoma and found that eBAG treatment promoted the induction of autophagy and reduction of tumor growth in mice. As a functional food ingredient, eBAG is a potential therapeutic agent for the treatment of hepatocellular carcinoma and esophageal cancer.

Targeting STAT3 potentiates CDK4/6 inhibitors therapy in head and neck squamous cell carcinoma

Anti-CDK4/6 therapy has been employed for the treatment for head and neck squamous cell carcinoma (HNSCC) with CDK4/6 hyperactivation, but the response rate is relatively low. In this study, we first showed that CDK4 and CDK6 was over-expressed and conferred poor prognosis in HNSCC. Moreover, in RB-positive HNSCC, STAT3 signaling was activated induced by CDK4/6 inhibition and STAT3 promotes RB deficiency by upregulation of MYC. Thirdly, the combination of Stattic and CDK4/6 inhibitor results in striking anti-tumor effect in vitro and in Cal27 derived animal models. Additionally, phospho-STAT3 levels negatively correlates with RB expression and predicts poor prognosis in patients with HNSCC. Taken together, our findings suggest an unrecognized function of STAT3 confers to CDK4/6 inhibitors resistance and presenting a promising combination strategy for patients with HNSCC.

Reprogramming tumor-associated macrophages and inhibiting tumor neovascularization by targeting MANF-HSF1-HSP70-1 pathway: An effective treatment for hepatocellular carcinoma

In advanced hepatocellular carcinoma (HCC) tissues, M2-like tumor-associated macrophages (TAMs) are in the majority and promotes HCC progression. Contrary to the pro-tumor effect of M2-like TAMs, M1-like TAMs account for a small proportion and have anti-tumor effects. Since TAMs can switch from one type to another, reprogramming TAMs may be an important treatment for HCC therapy. However, the mechanisms of phenotypic switch and reprogramming TAMs are still obscure. In this study, we analyzed differential genes in normal macrophages and TAMs, and found that loss of MANF in TAMs accompanied by high levels of downstream genes negatively regulated by MANF. MANF reprogrammed TAMs into M1 phenotype. Meanwhile, loss of MANF promoted HCC progression in HCC patients and mice HCC model, especially tumor neovascularization. Additionally, macrophages with MANF supplement suppressed HCC progression in mice, suggesting MANF supplement in macrophage was an effective treatment for HCC. Mechanistically, MANF enhanced the HSF1-HSP70-1 interaction, restricted HSF1 in the cytoplasm of macrophages, and decreased both mRNA and protein levels of HSP70-1, which in turn led to reprogramming TAMs, and suppressing neovascularization of HCC. Our study contributes to the exploration the mechanism of TAMs reprogramming, which may provide insights for future therapeutic exploitation of HCC neovascularization.

Cancer-associated fibroblasts derived fibronectin extra domain A promotes sorafenib resistance in hepatocellular carcinoma cells by activating SHMT1

Resistance to sorafenib, an effective first-line treatment for advanced hepatocellular carcinoma (HCC), greatly compromised the prognosis of patients. The extracellular matrix is one of the most abundant components of the tumor microenvironment. Beyond acting as a physical barrier, it remains unclear whether cell interactions and signal transduction mediated by the extracellular matrix contribute to sorafenib resistance. With the analysis of primary HCC organoid RNA-seq data combined with in vivo and in vitro experiments validation, we discovered that fibronectin extra domain A (FN-EDA) derived from cancer-associated fibroblasts played a critical role in sorafenib resistance. Mechanistically, FN-EDA stimulates the up-regulation of the key one-carbon metabolism enzyme SHMT1 in HCC cells via the TLR4/NF-κB signaling pathway, thereby countering the oxidative stress induced by sorafenib. Moreover, we reinforced the clinical significance of our discoveries by conducting in vivo assays with an immunodeficiency subcutaneous xenograft tumor model, which was established using primary cancer-associated fibroblasts derived from clinical HCC tissues, and through the analysis of HCC samples obtained from The Cancer Genome Atlas (TCGA) database. Our findings suggest that targeting the FN-EDA/SHMT1 pathway could be a potential strategy to improve sorafenib responsiveness in HCC patients.

Which is the best TACE agent for patients with different NLR hepatocellular carcinomas? A systematic review and network meta-analysis

BackgroundTransarterial chemoembolization (TACE) is a common treatment for hepatocellular carcinoma (HCC), but the best therapeutic agent for TACE treatment has not been determined. The neutrophil/lymphocyte ratio (NLR) is a systemic immune system marker; however, the ability of the NLR to predict the prognosis of patients with HCC is unknown, and no studies have been conducted to determine the most appropriate TACE regimen for HCC patients with different NLRs. MethodsThe PubMed, Embase, Web of Science, and CNKI databases were searched through May 28, 2023. Comparisons of overall survival (OS) among cohort studies with different NLRs and different TACE treatment regimens were performed with a random effects model. FindingsThirty-five studies involving 9210 patients were included in this meta-analysis. The results showed that Group 3–4 (NLR<2.5) patients had a significantly longer OS than Group 1–2 (NLR 2.5–5.0). Among the patients, Group 1–3 (NLR 2.0–5.0) patients had the best survival after treatment with adriamycin (lnHR (95 % CI = 0.48 [0.31, 0.75] and lnHR (95 % CI = 0.41 [0.19, 0.91]). Among the Group 4 patients (NLR<2.0), the best outcome was obtained with platinum + adriamycin (lnHR (95 % CI = 0.59 [0.45, 0.78]), followed by adriamycin. A subgroup analysis of TACE combined with other treatments showed that adriamycin combined with sorafenib was the most effective and superior to the other treatment agents. InterpretationThe NLR can be used to predict the prognosis of HCC patients treated with TACE; the higher the NLR is, the worse the prognosis. Adriamycin may be the best therapeutic agent for HCC patients treated with TACE.