Viable Tumor Research Articles

Mechanical Disruption by Focused Ultrasound Re-sensitizes ER+ Breast Cancer Cells to Hormone Therapy

ObjectiveTamoxifen is the most used agent to treat estrogen receptor-positive (ER+) breast cancer (BC). While it decreases the risk of cancer recurrence by 50%, many patients develop resistance to this treatment, culminating in highly aggressive disease. Tamoxifen resistance comes from the repression of ER transcriptional activity that switches the cancer cells to proliferation via nonhormonal signaling pathways. Here, we evaluate a potential strategy to overcome tamoxifen resistance by focused ultrasound (FUS), a noninvasive approach for the mechanical excitation of cancer cells. MethodsResistant and nonresistant ER+ BC cells and xenografts from patients with ER+ BC were treated with tamoxifen, FUS or their combination. The apoptosis, proliferation rate, gene expression and activity of estrogen receptor, and morphological changes were measured in treated cells and tissues. ResultsFUS caused the mechanical disruption of tamoxifen-resistant BC cells that in turn led to the upregulation of ERα-encoding gene expression and long-term re-sensitization of the cells to tamoxifen. Patient-derived xenografts treated with Tamoxifen and FUS demonstrated a significant reduction in tumor viability and proliferation and a strong structural damage to tumor cells and extracellular matrix. ConclusionFUS can improve ER+ BC treatment by re-sensitizing the cancer cells to tamoxifen.

Quantitative and Morphology-Based Deep Convolutional Neural Network Approaches for Osteosarcoma Survival Prediction in the Neoadjuvant and Metastatic Setting.

Necrosis quantification in the neoadjuvant setting using pathology slide review is the most important validated prognostic marker in conventional osteosarcoma. Herein, we explored three deep learning strategies on histology samples to predict outcome for OSA in the neoadjuvant setting. Our study relies on a training cohort from New York University (New York, NY) and an external cohort from Charles university (Prague, Czechia). We trained and validated the performance of a supervised approach that integrates neural network predictions of necrosis/tumor content, and compared predicted overall survival (OS) using Kaplan-Meier curves. Furthermore, we explored morphology-based supervised and self-supervised approaches to determine whether intrinsic histomorphological features could serve as a potential marker for OS in the setting of neoadjuvant. Excellent correlation between the trained network and the pathologists was obtained for the quantification of necrosis content (R2=0.899, r=0.949, p < 0.0001). OS prediction cutoffs were consistent between pathologists and the neural network (22% and 30% of necrosis, respectively). Morphology-based supervised approach predicted OS with p-value=0.0028, HR=2.43 [1.10-5.38]. The self-supervised approach corroborated the findings with clusters enriched in necrosis, fibroblastic stroma, and osteoblastic morphology associating with better OS (lg2HR; -2.366; -1.164; -1.175; 95% CI=[-2.996; -0.514]). Viable/partially viable tumor and fat necrosis were associated with worse OS (lg2HR;1.287;0.822;0.828; 95% CI=[0.38-1.974]). Neural networks can be used to automatically estimate the necrosis to tumor ratio, a quantitative metric predictive of survival. Furthermore, we identified alternate histomorphological biomarkers specific to the necrotic and tumor regions themselves which can be used as predictors.

Dynamic changes of radiological and radiomics patterns based on MRI in viable hepatocellular carcinoma after transarterial chemoembolization.

This study aims to analyze the magnetic resonance imaging (MRI) change patterns of viable hepatocellular carcinomas (HCCs) following the initial transarterial chemoembolization (TACE). A retrospective analysis of HCC patients' initial TACE from February 2015 to October 2022 across three centers and a clinical trial (NCT03113955) was conducted. The viability of residual HCCs at one and six months after TACE was evaluated using the LI-RADS Treatment Response Algorithm (LR-TRA) v2024. The radiological and radiomics features of post-TACE viable tumors between baseline and one-month, and between one- and six- months were compared using Wilcoxon signed-rank test and McNemar's test. A total of 160 viable tumors were included in the study. Viable tumors at one month after TACE exhibited higher T1WI intensity (P =.024), lower T2WI intensity (P =.005), fewer washout features (P <.001), smaller size (P <.001), and higher ADC values (P <.001) compared to baseline HCC imaging.A significant reduction in DWI intensity (P =.002) and ADC values (P <.001) were observed in viable tumors at one month compared to those at six months. There were 82 (45.1%) radiomics features that changed significantly between the baseline and one-month. Only three radiomics features showed statistically significant difference of viable tumors between one- and six-month. Compared to the baseline, viable HCCs after TACE demonstrated significant changes of imaging characteristics in a series of radiological and radiomics features at one- and six-month follow-ups. Clinically diagnosing of viable HCCs using radiological methods is challenging. A comprehensive analysis of these imaging characteristics can facilitate the accurate identification of viable tumors.

The Presence of Pigment Incontinence in Sinonasal Mucosal Melanoma.

Regression is an immunological phenomenon described in cutaneous melanoma whereby tumor is replaced with tumor-infiltrating lymphocytes, granulation tissue, and mature fibroblasts often accompanied by pigment incontinence (accumulation of melanin in the upper dermis). Pigment incontinence results in grossly pigmented lesions that may be mistaken for viable tumor and has not been described in sinonasal mucosal melanoma (SNMM). This study investigates the presence of regression and pigment incontinence in patients with SNMM. A retrospective chart review was conducted on SNMM patients from 2007 to 2023. Pathology slides from surgical resection were examined by two pathologists blinded to treatment information for the presence and extent of pigment-laden macrophages and other histopathologic features of regression. Seventeen patients with SNMM were included in this study who underwent surgical resection. Three patients received neoadjuvant therapy followed by surgical resection. Regression was present in 94% of patients and pigment incontinence was present in 65% of patients and occurred in both neoadjuvant treated patients and treatment naïve patients. All three patients with neoadjuvant treatment had evidence of pigment incontinence. This study highlights that SNMM often displays characteristics of regression. This study is one of the first to describe the presence of pigment incontinence in patients with SNMM. Pigment incontinence can be a part of the natural tumor life cycle and grossly pigmented lesions could easily be confused for melanoma especially after neoadjuvant therapy. Developing an understanding of regression and pigment incontinence within SNMM is important for diagnosis and clinical management. IV Laryngoscope, 2024.

Pre-transplant metabolic tumor volume predicts recurrence following liver transplantation for colorectal metastasis: A multicenter study.

Liver transplant (LT) for colorectal cancer liver metastases (CRLM) is increasingly popular, yet the ideal selection criteria remain unknown. Pre-transplant PET metabolic tumor volume (MTV) has been described as predicting recurrence, with a proposed cut-off of MTV ≥70cm3. This approach has not been validated. Patients undergoing LT for CRLM at two academic transplant centers (1/1/2017-12/1/2023) were included. PET-MTV was calculated by a staff radiologist from the most recent PET-scan before LT using the published protocol. Twenty-six patients were included. Median follow-up was 609 days (IQR 320-1069) and from PET to LT was 1.9 months (1.3-2.6). Nearly all (n=24, 92.3%) received living donor transplantation. Absolute recurrence rate was 30.8% (n=8). Actuarial unadjusted 1-, and 2-year RFS were 83% (n=15/18), and 62% (n=8/13); 1- and 2-year OS were 100% (n=18/18), and 85% (n=11/13).The incidence of recurrence-per-year follow-up was 0.35 when MTV ≥70cm3 versus 0.10 if MTV <70cm3 (P<0.001). Median RFS using Kaplan-Meier product-estimate was 0.83 years (95%CI 0.43-1.23) in MTV≥70cm3 versus 4.1 years (95%CI 2.90-5.22) when MTV<70cm3 (P<0.001); this was also associated with improved OS (P=0.003). MTV>70cm3 demonstrated HR=2.42 (95%CI 2.2-62.2, P=0.006) for association with RFS on univariate Cox-proportional hazards analysis, and an Area-Under-the-Curve (AUC)=0.771 (95%CI 0.560-0.981) for predicting recurrence (P=0.030)Nineteen patients (69.2%) had histologically viable tumor, which was associated with recurrence (43% vs. 0%, P=0.039) and reduced RFS (log-rank P=0.019). PET-MTV was associated with presence of histologically-viable tumor (AUC=0.763, 95%CI 0.583-0.944). PET-MTV ≥70cm3 was associated with reduced RFS and OS after LT for CRLM, confirming findings from the Norway group. This is likely due to its' ability to identify residual viable tumors, which are independently associated with recurrence. PET-MTV should be a key selection criterion prior to LT for CRLM.

The Correlation Patterns of miRNA Expression with Targeted mRNA Transcripts in Glioma Patients with Wild-Type and Mutated Isocitrate Dehydrogenase (IDH) Genotypes.

Low-grade gliomas are divided into two main genetic phenotypes based on the presence or absence of mutations in the isocitrate dehydrogenase (IDH) genes. The mutated IDH phenotype (IDHmut), in contrast to the wild-type phenotype (IDHwt), is characterized by a more positive response to pharmacological intervention and a significantly longer survival time. In this study, we analyzed the differential co-expression of 225,000 microRNA-mRNA pairs at the level of correlations between microRNA levels and their potential mRNA targets. Analysis of the associative relationships of individual representatives of the selected pairs revealed that the level of mRNAs encoded by the ELN, ARL4C, C9orf64, PLAT, and FKBP9 genes associated with aggressive progression of glioma was increased in the IDHwt group. Meanwhile, the levels of miRNA-182, miRNA-455, and miRNA-891a associated with the negative prognosis in glioma were generally increased in the IDHmut group. Most (16/21) of the detected 21 microRNA-mRNA pairs with significant difference in regulation between IDHwt and IDHmut glioma samples had a weak or moderate positive correlation in IDHmut samples and a negative correlation in IDHwt samples. Therefore, our findings indicate that glioma samples from the IDHmut group with a positive prognosis potentially have a significantly less pronounced ability to microRNA-mediated regulation. We further suggest that such physiological disorders can lead to reduced tumor viability, resulting in an increased ability of the host to resist the spread of a malignant transformation of this genetic phenotype.

SURG-44. TO PROCEED OR NOT TO PROCEED: THE IMPACT OF FROZEN SECTION PATHOLOGY ON INTRAOPERATIVE BRAIN BRACHYTHERAPY IMPLANTATION FOR RECURRENT GLIOBLASTOMA

Abstract BACKGROUND Glioblastoma (GBM) is a highly aggressive malignancy that recurs in up to 90% of patients following standard-of-care therapy, including surgical resection, concurrent chemoradiotherapy, and subsequent adjuvant chemotherapy. In cases of prior radiation therapy (RT) use, one option for localized, recurrent GBM (RGBM) is STaRT (Surgically Targeted Radiation Therapy) (GammaTile, GT Medical Technologies, Tempe AZ USA), a form of brachytherapy utilizing cesium-131 seeds implanted at the time of re-resection. One of the potential concerns with STaRT implantation for RGBM is that intraoperative frozen section pathology may demonstrate only necrosis, in which case further RT may not be advisable. This concern is often cited as a deterrent to offering an intraoperative brachytherapy treatment in RGBM cases. Herein we review the frequency of intraoperative frozen section diagnosis returning radiation necrosis leading to aborted GammaTile placement. METHODS The GammaTile Registry, a prospectively enrolling multi-center phase 4 study (NCT04427384), was assessed for all patients receiving intraoperative brachytherapy for RGBM from 10/2020 to 3/2024. Data regarding patient demographics, procedure details, and pathology were extracted and analyzed. RESULTS A total of 122 RGBM patients with a median age of 59 years (range 28-86) were scheduled for STaRT. Of these, 109 (89.3%) patients had confirmed prior radiation with a median RT dose of 60.0Gy (range 16-75). Only two (1.6%) planned cases of GammaTile placement were aborted after intraoperative frozen section pathology demonstrated extensive radiation necrosis without viable tumor. The patients had received fractionated RT to 55.8Gy and 60.0Gy, respectively. While both frozen samples were predominantly necrosis, the final pathology demonstrated foci of residual glioblastoma in both cases. CONCLUSIONS While it is uncommon in RGBM to abort STaRT due to intraoperative pathology indicating only radiation necrosis, careful consideration should be given when aborting the procedure as in this series final pathology ultimately demonstrated viable tumor cells.

IMMU-27. INHIBITION OF THE EXTRACELLULAR MATRIX PROTEIN EFEMP1/FIBULIN-3 REDUCES IMMUNOSUPPRESIVE SIGNALING IN TUMOR STEM CELLS AND INCREASES MACROPHAGE ACTIVATION AGAINST GLIOBLASTOMA

Abstract Glioblastoma tumors remain a formidable challenge for immune-based treatments because of their molecular heterogeneity, poor immunogenicity, and growth in the largely isolated and immunosuppresive neural environment. As the tumor grows, GBM cells change the composition and architecture of the neural extracellular matrix (ECM), affecting the mobility, survival, and function of immune cells such as tumor-associated microglia and infiltrated macrophages (TAMs). We have previously described the unique expression of the ECM protein EFEMP1/fibulin-3 in GBM compared to normal brain and demonstrated that this secreted protein promotes growth and resistance of the GBM stem cell (GSC) population. Here, we describe a novel immunomodulatory role of fibulin-3 and the immuno-boosting effects of targeting this ECM protein. Mice carrying fibulin-3-deficient intracranial tumors showed increased myeloid infiltration and reduced expression of TAM pro-tumoral markers (Arginase, CD206) compared to controls. The opposite was observed in orthotopic tumors overexpressing fibulin-3. In silico dataset analysis revealed positive correlation of fibulin-3 with an immunosuppresive signature in GBM, which was validated in GBM stem cells (GSCs). Accordingly, expression of fibulin-3 by GSCs promoted anti-inflammatory polarization of co-cultured macrophages. We further demonstrated that fibulin-3 regulated the expression of immunosuppresive signals (CSF-1, TGFbeta) and the innate immune checkpoint CD47 in GSCs via autocrine activation of NF-kB signaling. Immunosuppresive signals in GSCs were downregulated by knockdown of fibulin-3 or inhibition of this protein with an anti-fibulin-3 antibody (mAb428.2). Genetic or antibody-mediated targeting of fibulin-3 in GSCs co-cultured with macrophages (U937 and THP1 lines) increased macrophage phagocytosis and reduced the viability of the tumor cells. Furthermore, local delivery of mAb428.2 in mice carrying intracranial GBM resulted in increased infiltration of TAMs expressing pro-inflammatory markers and reducing tumor viability. Our findings show that anti-fibulin-3 approaches, which impact the tumor ECM, can diminish immunosuppression in GBM and boost innate immune responses against the tumor.

Exploring Extracellular Vesicle Surface Protein Markers Produced by Glioblastoma Tumors: A Characterization Study Using In Vitro 3D Patient-Derived Cultures.

Glioblastoma (GBM) is an aggressive brain cancer with limited treatment options. Extracellular vesicles (EVs) derived from GBM cells contain important biomarkers, such as microRNAs, proteins, and DNA mutations, which are involved in tumor progression, invasion, and resistance to treatment. Identifying surface markers on these EVs is crucial for their isolation and potential use in noninvasive diagnosis. This study aimed to use tumor-derived explants to investigate the surface markers of EVs and explore their role as diagnostic biomarkers for GBM. Tumor explants from nine GBM patients without IDH1/IDH2 mutations or 1p-19q co-deletion were cultured to preserve both tumor viability and cytoarchitecture. EVs were collected from the tumor microenvironment using differential centrifugation, filtration, and membrane affinity binding. Their surface protein composition was analyzed through multiplex protein assays. RNA-Seq data from TCGA and GTEx datasets, along with in silico single-cell RNA-seq data, were used to assess EV surface biomarker expression across large GBM patient cohorts. The in vitro model successfully replicated the tumor microenvironment and produced EVs with distinct surface markers. Biomarker analysis in large datasets revealed specific expression patterns unique to GBM patients compared with healthy controls. These markers demonstrated potential as a GBM-specific signature and were correlated with clinical data. Furthermore, in silico single-cell RNA-seq provided detailed insights into biomarker distribution across different cell types within the tumor. This study underscores the efficacy of the tumor-derived explant model and its potential to advance the understanding of GBM biology and EV production. A key innovation is the isolation of EVs from a model that faithfully mimics the tumor's original cytoarchitecture, offering a deeper understanding of the cells involved in EV release. The identified EV surface markers represent promising targets for enhancing EV isolation and optimizing their use as diagnostic tools. Moreover, further investigation into their molecular cargo may provide crucial insights into tumor characteristics and evolution.

The role of mesenchymal cells in cholangiocarcinoma.

The tumour microenvironment (TME) significantly influences tumour formation and progression through dynamic interactions. Cholangiocarcinoma (CCA), a highly desmoplastic tumour, lacks early diagnostic biomarkers and has limited effective treatments due to an incomplete understanding of its molecular pathogenesis. Investigating the TME's role in CCA progression could lead to better therapies. RNA sequencing was performed on seven CCA PDXs and their corresponding patient samples. Differential expression analysis was conducted, and Qiagen Ingenuity Pathway Analysis (IPA) was used to predict dysregulated pathways and upstream regulators. PDX and cell line-derived spheroids, with and without immortalised mesenchymal stem cells, were grown and analysed for morphology, growth, and viability. Histological analysis confirmed biliary phenotypes. RNA sequencing indicated upregulation of ECM-receptor interaction and PI3K-Akt pathways in the presence of MSCs, with several genes linked to poor survival. MSCs restored the activity of inhibited cancer-associated kinases (ICAKs). This study shows that adding MSCs to CCA spheroid models restores key paracrine signalling pathways lost in PDXs, enhancing tumour growth and viability. These findings highlight the importance of including stromal components in cancer models to improve pre-clinical studies.

080. Clinical Complete Resolution of Breast Cancer Achieved After Four Cycles of Chemotherapy: A Case Report of A 44-Year-Old Woman

Background: Breast cancer is a major cause of cancer-related deaths in women, with early detection critical for improving outcomes. In resource-limited settings, delayed diagnosis is common, leading to more advanced disease at presentation. This case report details a 44-year-old woman who achieved clinical complete resolution of her breast cancer after four cycles of chemotherapy. Case: The patient first noticed a marble-sized lump in the upper lateral quadrant of her left breast in August 2023. Despite the growing size of the mass, which increased to 5 cm over four months and became immobile, she delayed seeking medical care. Upon presentation, a biopsy confirmed a diagnosis of breast cancer. The patient was started on chemotherapy, receiving four cycles as a neoadjuvant treatment. Post-treatment examinations revealed a clincal complete resolution of the tumor, and she was subsequently scheduled for a mastectomy to remove any remaining disease and prevent recurrence. The post operative histopathology result; some viable tumor cells are still present in the left breast specimen and Sinus histiocytosis is present (no tumor cells are found) in all the lymph nodes examined. Conclusion: The clinical complete resolution observed in this patient following chemotherapy underscores its effectiveness in breast cancer treatment. Even though histopathological stated that there was minimal leftover cancer cells detected, which can be further treated with adjuvant chemoterapy. This case supports the need for increased awareness, early diagnosis, and access to chemotherapy for improving breast cancer outcomes.

Neoadjuvant Atezolizumab in Patients With Surgically Resectable Advanced Cutaneous Squamous Cell Carcinoma

PURPOSE To evaluate the feasibility of administering three doses of neoadjuvant atezolizumab before curative surgical resection in patients with advanced cutaneous squamous cell carcinoma (cSCC). PATIENTS AND METHODS This single-arm phase II trial included patients with cSCC of the head and neck with stage III or IV disease, or stage II lesions for which standard therapy would incur an unacceptable morbidity. Patients received up to three doses of atezolizumab at a fixed dose of 1,200 mg every 21 days before undergoing surgical resection. The primary end point was the percentage of patients able to complete three doses of therapy and be eligible for surgical resection without discontinuation due to toxicity or progression. Secondary end points included unconfirmed RECIST 1.1 response rate, pathological response rate (major and complete pathological response), and safety and tolerability of atezolizumab. RESULTS Twenty patients were enrolled and treated. Sixteen (80%) of 20 patients completed three doses of atezolizumab, and all patients were eligible for surgical resection. A pathological complete response was seen in seven (35%; 95% CI, 15.4 to 59.2) patients, and a major pathological response (&lt;10% viable tumor) was seen in four (20%; 95% CI, 5.7 to 43.7) patients. RECIST responses were seen in eight (40%; 95% CI, 19.1 to 64.0) patients, and one (5%) patient progressed. Grade 3 or higher adverse events were seen in one (5%) patient who developed pneumonitis after the first dose of atezolizumab. CONCLUSION Neoadjuvant atezolizumab is feasible and well tolerated in patients with advanced cSCC and results in a high rate of major and complete pathological responses.

Liver Transplantation for Intrahepatic Cholangiocarcinoma After Chemotherapy and Radioembolization: An Intention-To-Treat Study.

Liver transplantation (LT) is a potentially curative experimental treatment for unresectable intrahepatic cholangiocarcinoma (iCC). Pre-transplant downstaging may help defining tumor aggressiveness and drive patient selection. We report the preliminary results of LT for liver-limited unresectable iCC after sequential downstaging with systemic chemotherapy and radioembolization (SYS-TARE). In case of sustained disease stability after SYS-TARE, patients underwent surgical nodal sampling and, if negative, were listed for LT. In this study, 13 patients with unresectable iCC underwent downstaging with SYS-TARE. The median age was 70years and 77% were female. All had single bulky lesions at diagnosis. After SYS-TARE, 9 (69%) dropped out: 3 due to progressive disease after TARE with no response to second-line, 4 due to extrahepatic disease development and 2 due to positive nodal disease at pre-listing abdominal exploration. The median OS after dropout was 11.5 months. Four (31%) were successfully listed and transplanted. At pathology, viable tumor ranged from 30% to less than 5%. All four patients are alive and disease-free at 73, 40, 12, and 8months from LT. LT for unresectable iCC after downstaging with SYS-TARE appears to select suitable patients for LT, achieving optimal oncological outcomes in case of response to therapy and no lymphnodal spread.

Comprehensive Review of the Utility of Dynamic Contrast-Enhanced MRI for the Diagnosis and Treatment Assessment of Spinal Benign and Malignant Osseous Disease.

Conventional MRI is currently the preferred imaging technique for detection and evaluation of malignant spinal lesions. However, this technique is limited in its ability to assess tumor viability. Unlike conventional MRI, dynamic contrast-enhanced (DCE) MRI provides insight into the physiologic and hemodynamic characteristics of malignant spinal tumors and has been utilized in different types of spinal diseases. DCE has been shown to be especially useful in the cancer setting; specifically, DCE can discriminate between malignant and benign vertebral compression fractures as well as between atypical hemangiomas and metastases. DCE has also been shown to differentiate between different types of metastases. Furthermore, DCE can be useful in the assessment of radiation therapy for spinal metastases, including the prediction of tumor recurrence. This review considers data analysis methods utilized in prior studies of DCE-MRI data acquisition and clinical implications.

Postradiotherapy Response Assessment Using 18F-FDG PET/CT in Salivary Gland Carcinoma-A Multicenter Study.

This multicenter study investigates the efficacy of 18F-FDG PET/CT in postradiotherapy (post-RT) response evaluation in salivary gland carcinoma (SGC). We retrospectively reviewed 115 SGC patients who underwent definitive or adjuvant RT followed by 18F-FDG PET/CT between 2004 and 2021. Most tumors were parotid gland malignancies (50%). The most common histological subtypes were adenoid cystic (29%) and mucoepidermoid carcinomas (18%). The median follow-up was 65 months. Post-RT anatomic images (CT/MRI) revealed complete response (CR) in 51 patients (44%). Among 53 patients with partial response or stable disease, only 17 (32%) patients experienced locoregional recurrence, with a 5-year locoregional control rate of 69%. Post-RT 18F-FDG PET/CT documented metabolic CR in 81 patients (70%). Metabolic complete responders had significantly higher 5-year locoregional control (90% vs 43%), distant metastasis-free survival (80% vs 48%), progression-free survival (76% vs 24%), and overall survival rates (89% vs 42%) compared with non-complete responders (all P < 0.001), as confirmed in both univariate and multivariate analyses. It identified additional viable tumors in 18 cases (16%) and facilitated salvage local therapies in 7 patients (6%). The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of post-RT 18F-FDG PET/CT were 63%, 91%, 70%, 88%, and 84%, respectively, in predicting locoregional recurrence. 18F-FDG PET/CT showed significantly higher sensitivity (88% vs 36%, P = 0.011) in tumors with pre-RT SUVmax ≥7.39 compared with those with SUVmax <7.39. Post-RT 18F-FDG PET/CT demonstrates high negative predictive value and specificity, with metabolic CR predicting excellent outcomes. Additionally, it exhibits higher sensitivity for high-SUVmax SGC, facilitating early detection of viable tumors.

Fecal Microbiome Composition Correlates with Pathologic Complete Response in Patients with Operable Esophageal Cancer Treated with Combined Chemoradiotherapy and Immunotherapy.

Background: Preclinical and clinical data indicate that chemoradiotherapy (CRT) in combination with checkpoint inhibitors may prime an anti-tumor immunological response in esophageal cancer. However, responses to neoadjuvant therapy can vary widely and the key biomarkers to determine response remain poorly understood. The fecal microbiome is a novel and potentially modifiable biomarker of immunotherapy response, and both fecal and tumor microbes have been found to associate with outcomes in esophageal cancer. Methods: Fecal and tumor samples were collected from patients with stage II-III resectable esophageal or gastroesophageal junction carcinoma treated with neoadjuvant immune checkpoint inhibitors (ICIs) plus CRT prior to surgical resection. Microbiome profiles were analyzed by 16S rRNA amplicon sequencing and taxonomic data were integrated with fecal metabolite analysis to assess microbial function. Results: The fecal microbiome of patients with pathological complete response (PCR) grouped in distinct clusters compared to patients with residual viable tumor (RVT) by Bray-Curtis diversity metric. Integrated taxonomic and metabolomic analysis of fecal samples identified a sphingolipid and primary bile acid as enriched in the PCR, the levels of which correlated with several bacterial species: Roseburis inulinivorans, Ruminococcus callidus, and Fusicantenibacter saccharivorans. Analysis of the tumor microbiome profiles identified several bacterial genera previously associated with esophageal tumors, including Streptococcus and Veillonella. Conclusions: These results further characterize the fecal and tumor microbiome of patients with operable esophageal cancer and identify specific microbes and metabolites that may help elucidate how microbes contribute to tumor response with neoadjuvant CRT combined with ICI.

Neoadjuvant Therapy and Lung Cancer: Role of Pathologists.

Recent neoadjuvant clinical trials in lung cancer have demonstrated the survival benefits in carefully selected patients. Standardization of the assessment of pathologic response to neoadjuvant therapy in surgically resected specimens is required. To review the current pathology practices in the gross processing and microscopic assessment of surgically resected non-small cell lung carcinoma specimens after neoadjuvant therapy. PubMed publications and experience of the author. Gross processing of the surgically resected lung carcinoma after neoadjuvant therapy needs further refinement and standardization in clinical trials and in a real-world clinical practice. Microscopic assessment of the response includes quantification of viable tumor, necrosis, and stroma. The best approach would be to use a single standardized and most reproducible scoring system. Published studies on gross processing of lung carcinoma specimens in the neoadjuvant setting and microscopic assessment of pathologic response provide a good foundation for the future standardization of pathology practice.

Immunotherapy response induces divergent tertiary lymphoid structure morphologies in hepatocellular carcinoma.

Tertiary lymphoid structures (TLS) are associated with improved response in solid tumors treated with immune checkpoint blockade, but understanding of the prognostic and predictive value of TLS and the circumstances of their resolution is incomplete. Here we show that in hepatocellular carcinoma treated with neoadjuvant immunotherapy, high intratumoral TLS density at the time of surgery is associated with pathologic response and improved relapse-free survival. In areas of tumor regression, we identify a noncanonical involuted morphology of TLS marked by dispersion of the B cell follicle, persistence of a T cell zone enriched for T cell-mature dendritic cell interactions and increased expression of T cell memory markers. Collectively, these data suggest that TLS can serve as both a prognostic and predictive marker of response to immunotherapy in hepatocellular carcinoma and that late-stage TLS may support T cell memory formation after elimination of a viable tumor.

SASS6 promotes tumor proliferation and is associated with TP53 and immune infiltration in lung adenocarcinoma

The most common type of non-small cell lung cancer is lung adenocarcinoma (LUAD), which is characterized by high morbidity and poor survival. Up-regulation of SASS6 expression can lead to the progression of various malignant tumors. However, there are no relevant studies on the role of SASS6 in LUAD. SASS6 was highly expressed in most tumors, reflecting a good diagnostic value, and its overexpression in LUAD indicated discouraging overall prognosis. Functional enrichment analysis suggested that SASS6 was associated with cell cycle in LUAD. In addition, patients with high SASS6 expression had worse immune infiltration, but higher TMB and immune checkpoint, and higher sensitivity to multiple targeted drugs such as osimertinib. Cell experiments confirmed that knockdown of SASS6 could inhibit the viability of tumor cells.SASS6 has important value in the diagnosis of cancer. In particular, SASS6 is a crucial factor in the progression of LUAD, and has important clinical value, especially in the diagnosis, prognosis and treatment

Impact of select actionable genomic alterations on efficacy of neoadjuvant immunotherapy in resectable non-small cell lung cancer

BackgroundNeoadjuvant immune checkpoint inhibitors (ICIs) have improved survival outcomes compared with chemotherapy in resectable non-small cell lung cancer (NSCLC). However, the impact of actionable genomic alterations (AGAs) on the efficacy...