Cases Of Advanced Cancer Research Articles

Bioethical and Medical-Legal Challenges in Multimodal Cancer Treatment: Addressing Misinformation and Informal, Unregistered Advice

This article addresses the bioethical and medico-legal challenges in the multimodal treatment of cancer, emphasizing the growing gap between therapeutic advances and their clinical implementation. Many patients remain uninformed or lack access to advanced therapies, such as immunotherapy or targeted treatments, due to outdated practices in their healthcare centers. This situation often leads to frustration, as patients feel that not all potential treatment options have been explored. The right of patients to receive clear, informed, and transparent guidance on their treatment is highlighted, as well as the necessity for proper documentation of medical decisions to ensure traceability and protect both the patient and the medical professionals involved. The lack of information or bias directly impacts patient autonomy, limiting their ability to make well-founded decisions. The article also highlights the significant benefits of multimodal therapies, such as cytoreductive surgery and personalized immunotherapy, which have been shown to improve outcomes and quality of life in advanced cancer cases. It calls for treating physicians to act as guides or, when necessary, defer to specialized centers with proven expertise, thus avoiding limiting patients to conventional protocols. The need for a multidisciplinary approach is clear, with a committee of clinical oncologists, radiation-oncologists, surgical oncologists, and pathologists, alongside immuno- oncopathology specialists, being essential to the development of personalized, biologically driven therapies. Advances in cancer treatment confirm the importance of this integrated approach, particularly through collaboration between pathologists and clinical oncologists who have specialized in biotechnology and precision medicine.

Effect of Fluorescence Lymph Node Mapping on Improving Diagnostic Values of CT D3 Lymph Node Staging for Right-Sided Colon Cancer

Background/Objectives: This study evaluated the impact of fluorescence lymph node mapping (FLNM) using indocyanine green (ICG) on the diagnostic accuracy of preoperative computed tomography (CT) in right-sided colon cancer. Methods: A total of 218 patients who underwent laparoscopic right hemicolectomy with D3 lymph node dissection (LND) were analyzed: 86 patients in the FLNM group and 132 in the conventional surgery group. The FLNM technique allowed for enhanced intraoperative visualization of lymph node (LN) and more precise dissection, improving the identification of metastatic LNs. The diagnostic value of preoperative CT staging was assessed in both the FLNM and control groups by calculating the apparent prevalence, true prevalence, sensitivity, specificity, positive predictive value (PPV), negative predictive value, positive likelihood ratio (PLR), negative likelihood ratio, false positive and false negative proportions, and accuracy. Results: FLNM increased the accuracy of CT staging for detecting D3 LN metastasis in advanced cancer cases, with a higher PPV, PLR, and accuracy. In the FLNM group, the false-positive rate was significantly reduced, and the specificity was higher compared to the control group. Multivariate analysis identified FLNM as an independent factor associated with improved D3 LN metastasis detection. These findings suggest that incorporating FLNM into surgical procedures enhances the diagnostic value of preoperative CT by improving the precision of LND, particularly in patients with advanced colon cancer. Conclusions: The use of FLNM for D3 LND enhances the diagnostic accuracy of cN staging in right-sided colon cancer by improving surgical precision.

Comparative Transcriptomes of Canine and Human Prostate Cancers Identify Mediators of Castration Resistance.

Prostate cancer continues to be one of the most lethal cancers in men. While androgen deprivation therapy is initially effective in treating prostate cancer, most cases of advanced prostate cancer eventually progress to castration-resistant prostate cancer (CRPC), which is incurable. Similarly, the most aggressive form of prostatic carcinoma occurs in dogs that have been castrated. To identify molecular similarities between canine prostate cancer and human CRPC, we performed a comparative analysis of gene expression profiles. Through this transcriptomic analysis, we found that prostatic carcinoma in castrated dogs demonstrates an androgen-indifferent phenotype, characterised by low-androgen receptor and neuroendocrine-associated genes. Notably, we identified two genes, ISG15 and AZGP1, that were consistently up- and down-regulated, respectively, in both canine prostatic carcinoma and human CRPC. Additionally, we identified several other genes, including GPX3, S100P and IFITM1, that exhibited similar expression patterns in both species. Protein-protein interaction network analysis demonstrated that these five genes were part of a larger network of interferon-induced genes, suggesting that they may act together in signalling pathways that are disrupted in prostate cancer. Accordingly, our findings suggest that the interferon pathway may play a role in the development and progression of CRPC in both dogs and humans and chart a new therapeutic approach.

P9-4 Experiences with trastuzumab deruxtecan in 11 cases of advanced gastric cancer

P9-4 Experiences with trastuzumab deruxtecan in 11 cases of advanced gastric cancer

Evaluation of malignancy in gallbladder tumors using the apparent diffusion coefficient obtained by diffusion‑weighted MRI.

The utility of the apparent diffusion coefficient (ADC) of diffusion-weighted image (DWI) magnetic resonance imaging was examined for evaluating malignancy and prognosis in gallbladder tumors. A total of 63 patients (benign tumors, n=33; cancer, n=30) were included after surgical resection for gallbladder tumors, and their mean ADC values by DWI were obtained. Cases of advanced gallbladder cancer (n=25) were divided into ADCHigh and ADCLow groups, and clinicopathological factors were compared. In 63 cases, ADC values in advanced gallbladder cancer were significantly lower compared with benign tumors and non-advanced gallbladder cancer (P<0.05), and ADC values in early gallbladder cancer were also significantly lower compared with benign tumors (P<0.05). In 25 advanced gallbladder cancer cases, the ADCLow group tended to have a higher rate of advanced stage disease (P=0.09). Disease-free survival and overall survival (OS) of the ADCLow group were worse compared with the ADCHigh group (P<0.01). In the multivariate analysis of OS, poor differentiation and low ADC value were independent prognostic factors. ADC values may be useful for evaluating tumor malignancies in gallbladder tumors.

Comparative Transcriptomes of Canine and Human Prostate Cancers Identify Mediators of Castration Resistance.

Prostate cancer continues to be one of the most lethal cancers in men. While androgen-deprivation therapy is initially effective in treating prostate cancer, most cases of advanced prostate cancer eventually progress to castration-resistant prostate cancer (CRPC), which is incurable. Similarly, the most aggressive form of prostatic carcinoma occurs in dogs that have been castrated. To identify molecular similarities between canine prostate cancer and human CRPC, we performed a comparative analysis of gene expression profiles. Through this transcriptomic analysis, we found that prostatic carcinoma in castrated dogs demonstrate an androgen indifferent phenotype, characterized by low androgen receptor and neuroendocrine associated genes. Notably, we identified two genes, ISG15 and AZGP1 that were consistently up- and downregulated, respectively, in both canine prostatic carcinoma and human CRPC. Additionally, we identified several other genes, including GPX3, S100P, and IFITM1, that exhibited similar expression patterns in both species. Protein-protein interaction network analysis demonstrated that these 5 genes were part of a larger network of interferon-induced genes, suggesting that they may act together in signaling pathways that are disrupted in prostate cancer. Accordingly, our findings suggest that the interferon pathway may play a role in the development and progression of CRPC in both dogs and humans and chart a new therapeutic approach.

Usefulness of endoscopic ultrasound with bronchoscope-guided fine-needle aspiration for next-generation sequencing in patients with non-small cell lung cancer: A comparison with other bronchoscopic techniques

BackgroundNext-generation sequencing (NGS) is essential in treating advanced lung cancer. However, the effectiveness of endoscopic ultrasound with bronchoscope-guided fine-needle aspiration (EUS-B-FNA) in NGS remains unclear. This study examined the usefulness of EUS-B-FNA in lung cancer NGS cases where EUS-B-FNA was performed for specimen submission in a nationwide genomic screening platform (LC-SCRUM-Asia) and compared specimens collected using other bronchoscopy methods (endobronchial ultrasound-guided transbronchial needle aspiration [EBUS-TBNA] and EBUS-guided transbronchial biopsy with a guide sheath [EBUS-GS-TBB]) during the same period. MethodsWe retrospectively compared the NGS success rates of NGS, DNA and RNA yields for EUS-B-FNA, EBUS-TBNA, and EBUS-GS-TBB from the records of the patients recruited for the Lung Cancer Genomic Screening Project for Individualized Medicine (LC-SCRUM)-Asia. ResultsFifty-one patients were enrolled, and the NGS success rates were comparable for samples obtained by EUS-B-FNA, EBUS-TBNA, and EBUS-GS-TBB (100%, 90.9%, and 81.0%, respectively). Genetic alterations were detected in 73.7%, 90.9%, and 85.7% of patients, respectively, with druggable genetic alterations found in 31.6%, 72.7%, and 61.9% of patients, respectively. The DNA and RNA yields were significantly higher in EUS-B-FNA samples than in EBUS-GS-TBB samples (50.4 (interquartile range (IR): 15.45–72.35) ng/μl and 33.9 (IR: 9–76.8) ng/μl from EUS-B-FNA, and 3.3 (IR: 1.4–7.1) ng/μl and 15.1 (IR: 8.3–31.5) ng/μl from EBUS-GS-TBB, respectively, p < 0.05). ConclusionEUS-B-FNA emerges as a promising bronchoscopic method for obtaining adequate samples for NGS in advanced lung cancer cases.

The Role of Immunotherapy in the Management of Esophageal Cancer in Patients Treated with Neoadjuvant Chemoradiation: An Analysis of the National Cancer Database.

The current National Comprehensive Cancer Network advises neoadjuvant chemoradiotherapy followed by surgery for locally advanced cases of esophageal cancer. The role of immunotherapy in this context is under heavy investigation. Patients with esophageal adenocarcinoma were identified in the National Cancer Database (NCDB) from 2004 to 2019. Three groups were generated as follows: (a) no immunotherapy, (b) neoadjuvant immunotherapy, and (c) adjuvant immunotherapy. Overall survival was evaluated using the Kaplan-Meier method and Cox proportional hazard analysis, adjusting for previously described risk factors for mortality. Of the total 14,244 patients diagnosed with esophageal adenocarcinoma who received neoadjuvant chemoradiation, 14,065 patients did not receive immunotherapy, 110 received neoadjuvant immunotherapy, and 69 received adjuvant immunotherapy. When adjusting for established risk factors, adjuvant immunotherapy was associated with significantly improved survival compared to no immunotherapy and neoadjuvant immunotherapy during a median follow-up period of 35.2 months. No difference was noted among patients who received no immunotherapy vs. neoadjuvant immunotherapy in the same model. In this retrospective analysis of the NCDB, receiving adjuvant immunotherapy offered a significant survival advantage compared to no immunotherapy and neoadjuvant immunotherapy in the treatment of esophageal adenocarcinoma. The addition of neoadjuvant immunotherapy to patients treated with neoadjuvant chemoradiation did not improve survival in this cohort. Further studies are warranted to investigate the long-term outcomes of immunotherapy in esophageal cancer.

Successful Management of Upper Gastrointestinal Obstruction With Primary Advanced Ovarian Cancer.

Upper gastrointestinal obstruction is an extremely rare complication of primary ovarian cancer. We present a case of primary advanced ovarian cancer with gastroduodenal obstruction successfully managed with neoadjuvant chemotherapy (NAC) and conservative treatment. A 60-year-old woman was referred to our hospital for advanced ovarian cancer with upper gastrointestinal obstruction. Computed tomography and endoscopy revealed severe duodenal obstruction caused by dissemination. NAC was initiated with conservative management using a nasogastric tube and total parenteral nutrition (TPN). She was able to eat and TPN was stopped after three months. Complete resection was achieved with interval debulking surgery (IDS) not involving pancreatoduodenectomy, which would have been necessary for primary debulking surgery. There were no serious postoperative complications. NAC with conservative management can improve upper gastrointestinal obstruction in patients with primary advanced ovarian cancer. Furthermore, IDS is expected to allow complete resection, avoiding highly invasive surgeries.

Rural HIV Negative Young Women Presenting with Advanced FIGO Stages (iii and iv) of Early Onset Cancer of the Cervix Compared to their Urban Counterparts in Western Kenya – A Case Study of Jaramogi Oginga Odinga Teaching and Referral Hospital?

Background: In many Low and middle income countries, most patients present with advanced cases of cervical cancer (Figo Stages III and IV). The factors contributing to this have been studied and reported as being due to health seeking behaviours, lack of screening services and late diagnosis among others. Objective: This study aimed to explore the increase in incidences of early onset advanced cervical cancer in young HIV Negative rural women, as compared to their urban counterparts presenting at the Oncology Clinic of the hospital. Methodology: A mixed method study was undertaken of purposively recruited HIV negative patients, aged 13-35 years, presenting with Cancer of the Cervix in the 2020-2021 period of study. Findings: The study found out that, in the period 2020-2021, most patients presented to the hospital with early onset advanced cancer of the cervix, and 39 (64%) were diagnosed at FIGO Stages III and IV, while just 22 (36%) were diagnosed at Stages I and II. Conclusion: Our conclusion is that apparently due to the early routine cancer of the cervix screening of young HIV positive women, cases are being diagnosed very early, in the pre-cancer and early stages, leading to early treatment and remission, in turn leading to the increased contribution of young HIV negative women with advanced cancer of the cervix.

Efficacy and safety analysis of first-line tirelizumab combined with paclitaxel-containing chemotherapy regimen in 30 cases of real-world advanced gastric cancer in China.

e14643 Background: According to the latest global cancer statistics, gastric cancer is the 6th most common tumor with the highest incidence rate and the 5th highest mortality rate in the world. The primary treatment for advanced gastric cancer is still based on chemotherapy, and the median overall survival (OS) of patients treated with conventional chemotherapy is only 12 months. Recently, the rapid rise of immunotherapy has also brought new hope to gastric cancer patients. Many trials related to chemotherapy combined with immunotherapy for advanced gastric cancer are currently underway, which has been a hot research topic in recent years and has had auspicious positive results, such as the KEYNOTE-059 and CHECKMATE649 study. To reduce the burden of disease, the accessibility of innovative drugs has been significantly improved, providing more new clinical treatment ideas and options for Chinese patients with advanced gastric cancer. Methods: The study enrolled advanced gastric cancer (HER-2 negative) was treated with immune combination paclitaxel for first-line treatment, as follows: receiving intravenous albumin-conjugated paclitaxel (260 mg/m2) every 3 weeks; in combination with Tirelizumab (200 mg every three weeks), and after 4-6 cycles of treatment, Tirelizumab was maintained until disease progression or intolerance. The primary study endpoints were progression-free survival (PFS) and overall survival (OS), and the secondary endpoints were objective remission rate (ORR) and safety. Results: From July 2020 to August 2023, 30 patients received first-line immunization and paclitaxel-containing chemotherapy regimens at our center. The objective remission rate (ORR) was 40.9%, and the disease control rate (DCR) was 77.3%. The incidence of treatment-related grade 1-2 adverse reactions was: vomiting in 5 cases (16.7%), loss of appetite in 22 cases (73.3%), diarrhea in 10 cases (33.3%), transaminase elevation in 5 cases (16.7%), numbness of the hands and feet in 25 cases (83.3%), leukopenia in 7 cases (23.3%), and hemoglobin reduction in 16 cases (53.3%). hyperbilirubinemia in 2 cases (6.7%). Grade 3-4 adverse events and their incidence were: vomiting in 4 cases (13.3%), loss of appetite in 4 cases (13.3%), diarrhea in 1 case (3.3%), transaminase elevation in 2 cases (6.7%), leukopenia in 3 cases (10.0%), and hemoglobin reduction in 2 cases (6.7%). There were 3 cases of immunosuppressant-related adverse reactions (1 case of immunosuppressant-associated thyroiditis, 1 case of immunosuppressant-associated acute myocardial infarction, Conclusions: The first-line treatment of advanced gastric cancer with immune checkpoint inhibitors combined with paclitaxel-containing chemotherapy has a high rate of disease control, prolongs overall survival, has more clinical adverse reactions, is favored by grade 1-2 adverse reactions, and has a high degree of safety, and provides a new clinical idea for the first-line treatment of patients with advanced gastric cancer. Clinical trial information: KY2022-189-02.

Aldehyde Dehydrogenese-1 High Cancer Stem-like Cells/Cancer-initiating Cells Escape from Cytotoxic T Lymphocytes due to Lower Expression of Human Leukocyte Antigen Class 1.

Human gastric cancer stem-like cells (CSCs)/cancer-initiating cells can be identified as aldehyde dehydrogenase-high (ALDHhigh) cells. Cancer immunotherapy employing immune checkpoint blockade has been approved for advanced gastric cancer cases. However, the effectiveness of cancer immunotherapy against gastric CSCs/CICs remains unclear. This study aimed to investigate the susceptibility of gastric CSCs/CICs to immunotherapy. Gastric CSCs/CICs were isolated as ALDHhigh cells using the human gastric cancer cell line, MKN-45. ALDHhigh clone cells and ALDHlow clone cells were isolated using the ALDEFLUOR assay. ALDH1A1 expression was assessed via qRT-PCR. Sphere-forming ability was evaluated to confirm the presence of CSCs/CICs. A model neoantigen, AP2S1, was over-expressed in ALDHhigh clone cells and ALDHlow clone cells, and susceptibility to AP2S1-specific TCR-T cells was assessed using IFNγ ELISPOT assay. Three ALDHhigh clone cells were isolated from MKN-45 cells. ALDHhigh clone cells exhibited a stable phenotype in in vitro culture for more than 2 months. The High-36 clone cells demonstrated the highest sphere-forming ability, whereas the Low-8 cells showed the lowest sphere-forming ability. High-36 cells exhibited lower expression of HLA-A24 compared to Low-8 cells. TCR-T cells specific for AP2S1 showed lower reactivity to High-36 cells compared to Low-8 cells. High-36 cells and Low-8 cells represent novel gastric CSCs/CICs and non-CSCs/CICs, respectively. ALDHhigh CSCs/CICs evade T cells due to lower expression of HLA class 1.

Incomplete bowel obstruction caused by sigmoid colon cancer in an inguinal hernia: a case report

BackgroundMost colon cancers that develop in the intestinal tract within the inguinal hernia sac are identified by incarceration. However, treatment methods for these cases vary depending on the pathology. Cases showing perforation or abscess formation require emergency surgery for infection control, while cases with no infection generally involve oncological resection, with laparoscopic surgery also being an option. We encountered a case of Incomplete bowel obstruction secondary to sigmoid colon cancer within the hernial sac. We report the process leading to the selection of the treatment method and the surgical technique, along with a review of the literature.Case presentationA 79-year-old man presented to our hospital complaining of a left inguinal bulge (hernia) and pain in the same area. The patient had the hernia for more than 20 years. Using computed tomography, we diagnosed an incomplete bowel obstruction caused by a tumor of the intestinal tract within the hernial sac. Since imaging examination showed no signs of strangulation or perforation, we decided to perform elective surgery after a definitive diagnosis. After colonoscopy, we diagnosed sigmoid colon cancer with extra-serosal invasion; however, we could not insert a colorectal tube. Although we proposed sigmoid resection and temporary ileostomy, we chose the open Hartmann procedure because the patient wanted a single surgery. For the hernia, we simultaneously used the Iliopubic Tract Repair method, which does not require a mesh. Eight months after the surgery, no recurrence of cancer or hernia was observed.ConclusionsWe report a case of advanced sigmoid colon cancer with a long-standing inguinal hernia that later became incomplete bowel obstruction. Although previous studies have used various approaches among the available surgical methods for cancer within the hernial sac, such as inguinal incision, laparotomy, and laparoscopic surgery, most hernias are repaired during the initial surgery using a non-mesh method. For patients with inguinal hernias that have become difficult to treat, the complications of malignancy should be taken into consideration and the treatment option should be chosen according to the pathophysiology.

Experiences of family caregivers in dealing with cases of advanced breast cancer: a qualitative study of the sociocultural context in Punjab, Pakistan

BackgroundPatients with advanced breast cancer require consistent help and support from family caregivers. These caregivers often endure financial burdens and psychological stress, with their experiences significantly influenced by sociocultural factors. This study aims to explore the experiences of family caregivers of advanced breast cancer patients in Punjab province, Pakistan.MethodsData was collected through in-depth interviews with fifteen family caregivers of advanced breast cancer patients in three major cities of Punjab, Pakistan. Caregivers, who had been in close contact with the patient for the last two years, were purposively sampled from five major hospitals. The data was analyzed using thematic analysis.ResultsThe study revealed that the experiences of family caregivers are deeply rooted in the sociocultural context. Key themes identified include social responsibility and cultural reciprocity norms; limited awareness and mobility options for caregivers; financial responsibility and strain; impacts of beauty myths and shyness on caregiving attitudes and decisions; the stressful and emotional nature of caregiving; treatment perspectives influenced by social groups; challenges in consulting male physicians and associated stigma; the role of religious beliefs in caregiving; and stress management, with religion often being a coping mechanism. These factors can contribute to delayed treatment decisions for patients.ConclusionsFamily caregivers are crucial in facilitating timely treatment decisions for advanced breast cancer patients in the Pakistani context. To minimize treatment delays and alleviate caregiver stress, addressing sociocultural barriers in care-seeking is essential. A tailored approach, considering sociocultural and religious factors, is imperative for the management and early diagnosis of breast cancer, necessitating appropriate policymaking and implementation.

Evaluating Pedicled Pectoralis Major Myocutaneous Flap Reconstructions for Oral Malignancy and the Influence of Laterally Based Rotational Advancement Flap on Donor Site Integrity and Nipple Position in Male Patients.

Oral cancer poses a significant health burden, particularly in the male population of India. This study focuses on evaluating the outcomes of 48 pedicled Pectoralis major myocutaneous (PMMC) flap reconstructions in male patients with oral malignancy. Given the challenges associated with microvascular flap reconstructions, especially in advanced cancer cases, older patients, and resource-constrained settings, the PMMC flap still serves as a valuable alternative. The study introduces a novel approach by incorporating a laterally based rotational advancement flap (LBRA) to address donor site integrity and decrease the nipple-areolar complex (NAC) displacement. Traditionally, PMMC flap designs tend to cause inward shifting of the NAC during chest donor site closure, impacting the aesthetic outcome. Surgical techniques involved wide local resection, neck dissection, and PMMC flap reconstruction. The Flap design included a horizontal orientation with adjustments based on defect location. Additionally, a laterally based rotational flap from the chest aided in donor site closure. Results demonstrate the versatility and reliability of PMMC flap reconstructions, with no total flap necrosis or major complications observed in the 48 cases. The LBRA technique effectively mitigated NAC displacement. The study contributes to the existing literature by providing insights into the advantages of PMMC flap reconstructions and introducing a technique to optimize donor site closure and decrease the medial shifting of the nipple. The adaptability, reliable vascular supply, and simplified learning curve make the PMMC flap a preferred choice in resource-constrained settings with high patient demand. In conclusion, this research underscores the continued relevance and effectiveness of the PMMC flap in head and neck reconstruction, offering satisfactory cosmetic and functional results. The introduction of the LBRA technique adds a nuanced dimension to improve outcomes, particularly in male patients with oral malignancy.

“Accepting Unexpected Health Realities”: Exploring the Life Experiences of Ovarian Cancer Patients – A Qualitative Study

Introduction: Among women, ovarian cancer is the eighth most frequent cancer globally and the fifth leading cause of cancer-related deaths in women. Ovarian cancer is termed the "silent killer" because of its slow onset and unclear symptoms. Most of the advanced cases of ovarian cancer were found due to poor screening. The main objective of this study was to understand the emotional experiences, coping and resilience of patients undergoing ovarian cancer treatment. Methods: This qualitative study employs a phenomenological approach to explore the life experiences of ovarian cancer patients. An in-depth interview was conducted among patients undergoing cancer treatment. A total of 11 participants were included in this study. Thematic analysis was done. Results: The analysis of the data revealed eight main themes and 32 sub-themes that were characterized based on the experiences of cancer patients: 1) Misconceptions about symptoms, 2) Barriers in accessing healthcare, 3) Physical struggles, 4) Emotional turmoil, 5) Social issues, 6) Hope giving factors, 7) Sacrifice for family well-being, and 8) Emotional resilience. Conclusion: One of the key findings of this study is the importance of accepting unexpected health realities. This study shows the emotional journey of accepting difficult realities and mainly trusting medical professionals to guide one through treatment. Develop targeted educational campaigns to raise awareness about the symptoms of ovarian cancer and dispel common misconceptions.

Mesothelin promotes brain metastasis of non-small cell lung cancer by activating MET

BackgroundBrain metastasis (BM) is common among cases of advanced non-small cell lung cancer (NSCLC) and is the leading cause of death for these patients. Mesothelin (MSLN), a tumor-associated antigen expressed in many solid tumors, has been reported to be involved in the progression of multiple tumors. However, its potential involvement in BM of NSCLC and the underlying mechanism remain unknown.MethodsThe expression of MSLN was validated in clinical tissue and serum samples using immunohistochemistry and enzyme-linked immunosorbent assay. The ability of NSCLC cells to penetrate the blood-brain barrier (BBB) was examined using an in vitro Transwell model and an ex vivo multi-organ microfluidic bionic chip. Immunofluorescence staining and western blotting were used to detect the disruption of tight junctions. In vivo BBB leakiness assay was performed to assess the barrier integrity. MET expression and activation was detected by western blotting. The therapeutic efficacy of drugs targeting MSLN (anetumab) and MET (crizotinib/capmatinib) on BM was evaluated in animal studies.ResultsMSLN expression was significantly elevated in both serum and tumor tissue samples from NSCLC patients with BM and correlated with a poor clinical prognosis. MSLN significantly enhanced the brain metastatic abilities of NSCLC cells, especially BBB extravasation. Mechanistically, MSLN facilitated the expression and activation of MET through the c-Jun N-terminal kinase (JNK) signaling pathway, which allowed tumor cells to disrupt tight junctions and the integrity of the BBB and thereby penetrate the barrier. Drugs targeting MSLN (anetumab) and MET (crizotinib/capmatinib) effectively blocked the development of BM and prolonged the survival of mice.ConclusionsOur results demonstrate that MSLN plays a critical role in BM of NSCLC by modulating the JNK/MET signaling network and thus, provides a potential novel therapeutic target for preventing BM in NSCLC patients.

Liquid biopsy for gastric cancer: Techniques, applications, and future directions.

After the study of circulating tumor cells in blood through liquid biopsy (LB), this technique has evolved to encompass the analysis of multiple materials originating from the tumor, such as nucleic acids, extracellular vesicles, tumor-educated platelets, and other metabolites. Additionally, research has extended to include the examination of samples other than blood or plasma, such as saliva, gastric juice, urine, or stool. LB techniques are diverse, intricate, and variable. They must be highly sensitive, and pre-analytical, patient, and tumor-related factors significantly influence the detection threshold, diagnostic method selection, and potential results. Consequently, the implementation of LB in clinical practice still faces several challenges. The potential applications of LB range from early cancer detection to guiding targeted therapy or immunotherapy in both early and advanced cancer cases, monitoring treatment response, early identification of relapses, or assessing patient risk. On the other hand, gastric cancer (GC) is a disease often diagnosed at advanced stages. Despite recent advances in molecular understanding, the currently available treatment options have not substantially improved the prognosis for many of these patients. The application of LB in GC could be highly valuable as a non-invasive method for early diagnosis and for enhancing the management and outcomes of these patients. In this comprehensive review, from a pathologist's perspective, we provide an overview of the main options available in LB, delve into the fundamental principles of the most studied techniques, explore the potential utility of LB application in the context of GC, and address the obstacles that need to be overcome in the future to make this innovative technique a game-changer in cancer diagnosis and treatment within clinical practice.

Establishment and characterization of multiple patient-derived organoids from a case of advanced endometrial cancer.

Patient-derived organoids (PDOs) retain the original tumor's characteristics to a large degree and allow direct evaluation of the drug sensitivity, thereby emerging as a valuable resource for both basic and preclinical researches. Whereas most past studies stereotypically adopted a single PDO as an avatar of the patient, it remains to be investigated whether this assumption can be justified even for the tumor with spatial diversity. To address this issue, we established and characterized multiple PDOs originating from various sites of a patient with advanced uterine carcinosarcoma (UCS). Specifically, cancer cells were separately sampled from three sites; resected UCS tumor tissue, the peritoneal lavage fluid, and an intra-uterine brushing of the tumor. The three derived PDOs were morphologically undistinguishable, displaying typical carcinoma organoids-like appearance, but two of them proliferated at a faster rate. The primary tumor harbored mutations in TP53 and STK11 along with amplifications in CCNE1, ERBB2, and KRAS. These two mutations and the CCNE1 amplification were detected in all PDOs, while either KRAS or ERBB2 amplification was selectively observed in each PDO in a mutually exclusive manner. Observed intra-tumor heterogeneity in HER2 expression was differentially reproduced in the PDOs, which mirrored each PDO's sensitivity to HER2 inhibitors. Inter-PDO heterogeneity was also evident in sensitivity to standard cytotoxic agents. Lastly, a drug screening identified four candidate reagents commonly effective to all PDOs. Collectively, we showed that multiple PDOs could help reproduce the spatial diversity of a tumor and serve as a valuable resource in UCS research in many respects.

Abstract 7135: Preclinical effects of Tumor Treating Fields (TTFields) with PARP inhibitors in ovarian cancer

Abstract Purpose: Among gynecological malignancies, ovarian cancer is the leading cause of mortality. Poly (ADP-ribose) polymerase inhibitors (PARPi) represent standard-of-care treatment for selected cases of advanced epithelial ovarian cancer. PARPi exhibit sensitivity in homologues recombination deficient (HRD) tumors, in which there are mutations in the Fanconi Anemia (FA)-BRCA pathway, while about 75% of ovarian cancer patients are homologues recombination proficient (HRP). TTFields are non-invasive electric fields that disrupt cellular processes critical for cancer cell viability and tumor progression. Recent research showed that TTFields induce an HRD-like state (also known as BRCAness state) in various cancer types. The current study aims to investigate the impact of TTFields applied together with PARPi in ovarian cancer preclinical models. Methods: In vitro, A2780 (HRP), OVCAR3 (HRD), and A2780cis (platinum-resistant) ovarian cancer cells were treated with TTFields (1 V/cm RMS, 200 kHz, 72 h), alone or with addition of PARPi (olaparib or niraparib, at various concentrations). Efficacy was measured by analyzing cell count, colony formation, and apoptosis induction. The overall effect was calculated by multiplying cell count with colony formation. TTFields-treated cells were evaluated for the expression of FA-BRCA pathway proteins and for formation of γH2AX, a DNA damage marker, using Western blot and fluorescent microscopy, respectively. In vivo, ID8-fLuc (HRP) cells were inoculated intraperitoneally to 6-8-week-old C57BL/6 mice. Seven days post inoculation, mice were treated with sham-vehicle, TTFields, olaparib (50 mg/kg), or both over a period of four weeks. Tumor growth was analyzed using bioluminescent imaging at treatment cessation, and survival analysis was performed. Results: TTFields application resulted in reduced cell count, increased overall effect, and increased apoptosis in vitro. When TTFields were applied together with PARPi, a high and moderate synergistic interaction was shown respectively the BRCA wild-type A2780 cells and the platinum-resistant A2780cis cells. However, in the BRCA mutant OVCAR-3 cells the effect was additive. A downregulation of FA-BRCA protein expression was confirmed after TTFields treatment of the ovarian cells, with consequent DNA damage. In the tumor-bearing mice, TTFields and olaparib co-treatment resulted in reduced tumor volume and a survival benefit relative to the monotherapies and to control-treated mice. Conclusions: The data suggest potential advantages for TTFields concomitant with PARPi in ovarian cancer, even without underlying BRCA mutations - consistent with the BRCAness state induced by TTFields - and also suggests benefits in platinum-resistant ovarian cancer. Citation Format: Yani Berckmans, Hila Ene, Kerem Ben-Meir, Antonia Martinez-Conde, Roni Monin, Bieke Van den Ende, Sara Van Mechelen, Roni Frechtel-Gerzi, Hila Gabay, Rotem Engelman, Eyal Dor-On, Adi Haber, Moshe Giladi, Uri Weinberg, Yoram Palti, Ignace Vergote, An Coosemans. Preclinical effects of Tumor Treating Fields (TTFields) with PARP inhibitors in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7135.