Viable Tumor Research Articles

CT/MRI technical pitfalls for diagnosis and treatment response assessment using LI-RADS and how to optimize.

Hepatocellular carcinoma (HCC), the most common primary liver cancer, is a significant global health burden. Accurate imaging is crucial for diagnosis and treatment response assessment, often eliminating the need for biopsy. The Liver Imaging Reporting and Data System (LI-RADS) standardizes the interpretation and reporting of liver imaging for diagnosis and treatment response assessment, categorizing observations using defined categories that are based on the probability of malignancy or post-treatment tumor viability. Optimized imaging protocols are essential for accurate visualization and characterization of liver findings by LI-RADS. Common technical pitfalls, such as suboptimal postcontrast phase timing, and MRI-specific challenges like subtraction misregistration artifacts, can significantly reduce image quality and diagnostic accuracy. The use of hepatobiliary contrast agents introduces additional challenges including arterial phase degradation and suboptimal uptake in advanced cirrhosis. This review provides radiologists with comprehensive insights into the technical aspects of liver imaging for LI-RADS. We discuss common pitfalls encountered in routine clinical practice and offer practical solutions to optimize imaging techniques. We also highlight technical advances in liver imaging, including multi-arterial MR acquisition and compressed sensing. By understanding and addressing these technical aspects, radiologists can improve accuracy and confidence in the diagnosis and treatment response assessment for hepatocellular carcinoma.

PERITONEAL KERATIN GRANULOMAS MIMICKING PERITONEAL CARCINOMATOSIS: A POTENTIAL DIAGNOSTIC PITFALL

Abstract Introduction/Objective Keratin granulomas from a primary uterine cancer can present as peritoneal tumor nodules, mimicking peritoneal carcinomatosis. Endometrial adenocarcinomas with viable peritoneal tumor implants and/or involvement of bladder or bowel mucosa are categorized as stage IV disease. We present a rare case of endometrial adenocarcinoma of the uterus with squamous differentiation and multiple peritoneal nodules of keratin granulomas, masquerading as peritoneal carcinomatosis. Methods/Case Report A 68-year-old female with insignificant past medical history presented with complaints of postmenopausal bleeding for the past four months. Physical examination was unremarkable. Transvaginal ultrasound showed a 4.9 cm echogenic mass in the uterus. The endometrial biopsy showed squamous debris with atypical cells suspicious of malignancy. Endometrial curettings revealed endometrial adenocarcinoma, endometrioid type with squamous differentiation, FIGO Grade 1. Subsequently, she underwent hysterectomy with bilateral salpingo- oophorectomy. Intraoperatively, multiple suspicious nodules on the sigmoid colon and in the pelvis were identified, of which excisional biopsies and pelvic peritoneal washing were taken. Microscopic examination of the resection confirmed endometrial adenocarcinoma, FIGO Grade 1, nuclear grade 1, with extensive foreign body giant cell reaction to dead squamous cells (ghost cells). Cytologic examination of the peritoneal washing was unremarkable and excisions of the sigmoid serosal and peritoneal nodules showed pink eosinophilic laminated nodules surrounded by inflammatory cells including plasma cells, lymphocytes and multinucleated giant cells without any viable tumor cells. Results (if a Case Study enter NA) NA Conclusion Keratin granulomas are a foreign body reaction to keratin deposition from the squamous component of endometrioid adenocarcinoma. The pathogenesis of this foreign body response to keratin is considered to be a trans- tubal spread of keratin through retrograde shedding from the fallopian tubes. In the absence of viable tumor cells, it appears to have no negative prognostic significance. Careful microscopic examination of peritoneal keratin granulomas is imperative to avoid erroneous upstaging of the tumor and the subsequent advanced treatment.

A case of neoadjuvant targeted therapy with pralsetinib for locally advanced lung adenocarcinoma with RET fusion mutation

This case report details the successful treatment of a 68-year-old male patient with locally advanced RET-rearranged lung adenocarcinoma using neoadjuvant pralsetinib. The patient initially presented with a suspicious right upper lobe nodule, which was later diagnosed as lung adenocarcinoma following genetic testing that revealed a RET exon 12 fusion. After 2 months of neoadjuvant treatment with pralsetinib, a significant radiological response was observed, with a reduction in tumor size and metabolic activity. Subsequently, the patient underwent video-assisted thoracoscopic right upper lobectomy and mediastinal lymph node dissection. Postoperative pathological analysis revealed a major pathological response, with only 5% residual tumor cells in the primary lesion and no viable tumor cells in the lymph nodes. Postoperative pathological staging of TNM was ypT1aN0M0, stage IA1(AJCC, 8th edition). The patient recovered well after surgery, demonstrating the potential efficacy of neoadjuvant pralsetinib in locally advanced RET-rearranged lung adenocarcinoma. However, further clinical validation is required to establish the role of neoadjuvant targeted therapy and postoperative adjuvant therapy in this patient population.

A case of salvage surgery following chemoradiotherapy and durvalumab for initially unresectable superior sulcus tumor with N3 involvement

BackgroundDurvalumab after chemoradiation (PACIFIC regimen) provides favorable treatment outcomes for unresectable stage III non-small cell lung cancer (NSCLC). The feasibility of salvage surgery after the PACIFIC regimen has been reported in some studies; however, its efficacy remains unclear. We herein present the first case of salvage surgery after the PACIFIC regimen for a superior sulcus tumor with N3 involvement, in which a pathological complete response was achieved.Case presentationA 53-year-old man with a left superior sulcus tumor with N3 (# 1L, #4R) involvement (adenocarcinoma, clinical T3N3M0/IIIC) underwent concurrent chemoradiotherapy (2 cycles of cisplatin plus vinorelbine with 60 Gy radiotherapy) followed by durvalumab treatment for 1 year at a previous hospital. The PACIFIC regimen provided a significant primary tumor shrinkage (diameter 3.1 cm to 0.5 cm) with the disappearance of 18F-fluorodeoxyglucose uptake in all nodes. Six months after the end of the PACIFIC regimen, only the primary tumor showed enlargement (diameter 0.5 cm to 2.0 cm). Accordingly, local tumor recurrence was suspected. Salvage surgery (left upper lobectomy with combined chest wall resection [1st to 4th rib]) was performed. The histological examination revealed no viable tumor cells (ypT0N0M0). At 7 months after salvage surgery, the patient remains alive with no signs of tumor recurrence.ConclusionsThe present case suggests that salvage surgery may be feasible after the PACIFIC regimen for superior sulcus tumors. A long-term follow-up is essential to determine the efficacy of salvage surgery.

Concordance of Whole-Slide Imaging and Conventional Light Microscopy for Assessment of Pathologic Response Following Neoadjuvant Therapy for Lung Cancer

Pathologic response is an end point in many ongoing clinical trials for neoadjuvant regimens, including immune checkpoint blockade and chemotherapy. Whole-slide scanning of glass slides generates high-resolution digital images and allows for remote review and potential measurement with image analysis tools, but concordance of pathologic response assessment on digital scans compared with that on glass slides has yet to be evaluated. Such a validation goes beyond previous concordance studies, which focused on establishing surgical pathology diagnoses, as it requires quantitative assessment of tumor, necrosis, and regression. Further, as pathologic response assessment is being used as an end point, such concordance studies have regulatory implications. The purpose of this study was 2-fold, which was as follows: first, to determine the concordance between pathologic response assessed on glass slides and that assessed on digital scans, and second, to determine if pathologists benefited from using measurement tools when determining pathologic response. To that end, hematoxylin and eosin–stained glass slides from 64 non–small cell lung carcinoma specimens were visually assessed for percent residual viable tumor (%RVT). The sensitivity and specificity for digital vs glass reads of pathologic complete response (0% RVT) and major pathologic response (≤10% RVT) were all >95%. When %RVT was considered as a continuous variable, the intraclass correlation coefficient of digital vs glass reads was 0.94. The visual assessments of pathologic response were supported by pathologist annotations of residual tumor and tumor bed areas. In a separate subset of hematoxylin and eosin–stained glass slides, several measurement approaches to quantifying %RVT were performed. Pathologist estimates strongly reflected measured %RVT. This study demonstrates the high level of concordance between glass slides evaluated using light microscopy and digital whole-slide images for pathologic response assessments. Pathologists did not require measurement tools to generate robust %RVT values from slide annotations. These findings have broad implications for improving clinical workflows and multisite clinical trials.

Évaluation de la réponse thérapeutique par TEP-FDG des cancers solides (critères PERCIST 1.0)

18F-Fluoro-Deoxyglucose (FDG) Positron Emission Tomography (PET) is an imaging technique used to study glucose metabolism in cells. It is particularly useful in oncology, especially for initial diagnosis and the detection of recurrence. Thanks to its functional approach to tissues, its use has evolved towards the evaluation of anticancer treatments, both in a personalized approach to patients and as part of clinical trials of new biotherapies. This technique provides additional information compared to conventional imaging, which is not always able to assess tumor viability of potentially necrotic or fibrotic residual masses after treatment. However, the use of FDG-PET requires a rigorous methodology, both for the performance of the studies and for their interpretation. Based on a large body of literature, interpretation criteria for solid tumors have been published and updated. PERCIST 1.0 (Positron Emission Tomography Response Criteria In Solid Tumors), proposed by an American task force in 2009, aims to clarify and standardize practice. These criteria will evolve according to the specificities of new biotherapies such as immunotherapy.

Sorafenib plus memory-like natural killer cell immunochemotherapy boosts treatment response in liver cancer

BackgroundHeterogeneity of hepatocellular carcinoma (HCC) presents significant challenges for therapeutic strategies and necessitates combinatorial treatment approaches to counteract suppressive behavior of tumor microenvironment and achieve improved outcomes. Here, we employed cytokines to induce memory-like behavior in natural killer (NK) cells, thereby enhancing their cytotoxicity against HCC. Additionally, we evaluated the potential benefits of combining sorafenib with this newly developed memory-like NK cell (pNK) immunochemotherapy in a preclinical model.MethodsHCC tumors were grown in SD rats using subcapsular implantation. Interleukin 12/18 cytokines were supplemented to NK cells to enhance cytotoxicity through memory activation. Tumors were diagnosed using MRI, and animals were randomly assigned to control, pNK immunotherapy, sorafenib chemotherapy, or combination therapy groups. NK cells were delivered locally via the gastrointestinal tract, while sorafenib was administered systemically. Therapeutic responses were monitored with weekly multi-parametric MRI scans over three weeks. Afterward, tumor tissues were harvested for histopathological analysis. Structural and functional changes in tumors were evaluated by analyzing MRI and histopathology data using ANOVA and pairwise T-test analyses.ResultsThe tumors were allowed to grow for six days post-cell implantation before treatment commenced. At baseline, tumor diameter averaged 5.27 mm without significant difference between groups (p = 0.16). Both sorafenib and combination therapy imposed greater burden on tumor dimensions compared to immunotherapy alone in the first week. By the second week of treatment, combination therapy had markedly expanded its therapeutic efficacy, resulting in the most significant tumor regression observed (6.05 ± 1.99 vs. 13.99 ± 8.01 mm). Histological analysis demonstrated significantly improved cell destruction in the tumor microenvironment associated with combination treatment (63.79%). Interestingly, we observed fewer viable tumor regions in the sorafenib group (38.9%) compared to the immunotherapy group (45.6%). Notably, there was a significantly higher presence of NK cells in the tumor microenvironment with combination therapy (34.79%) compared to other groups (ranging from 2.21 to 26.50%). Although the tumor sizes in the monotherapy groups were similar, histological analysis revealed a stronger response in pNK cell immunotherapy group compared to the sorafenib group.ConclusionsExperimental results indicated that combination therapy significantly enhanced treatment response, resulting in substantial tumor growth reduction in alignment with histological analysis.

Multidisciplinary approaches to downstaging hepatocellular carcinoma: present and future.

Downstaging of hepatocellular carcinoma (HCC) is typically defined as the reduction in size or number of viable tumors through locoregional therapy (LRT), aiming to meet the established criteria for liver transplantation (LT). According to the Barcelona Clinic Liver Cancer (BCLC) staging system, a subgroup of patients with BCLC-B may benefit most from downstaging therapies. The United Network Organ Sharing downstaging protocol identifies potential candidates for downstaging by setting out 'inclusion criteria' and defining 'successful downstaging.' Additionally, the protocol considers factors related to tumor biology, such as an alphafetoprotein level <500 ng/mL after LRT. Reports indicate that successful downstaging rates following LRT are about 50%, with post- LT recurrence rates comparable to those of patients within the Milan criteria. A comprehensive multicenter US study on 10-year outcomes post-LT after downstaging showed 10-year post-LT survival and recurrence rates of 52.1% and 20.6%, respectively, for patients whose disease was downstaged; this compares to 61.5% and 13.3% for those consistently within the Milan criteria. Recently, the development of effective systemic treatments for HCC, such as immuno-oncologic agents, has provided additional opportunities for downstaging. Numerous clinical trials are exploring a multidisciplinary approach (MDA) combining LRT and systemic therapy. Although concrete evidence of the superiority of MDA for HCC downstaging is lacking, some retrospective studies and phase I and II trials have shown promising results regarding the efficacy and safety of MDA for this purpose. In this review, we will also discuss the future of MDA protocols in downstaging for improved clinical outcomes.

Survival impact of pathologic features after salvage lung resection following definitive chemoradiotherapy or systemic therapy for initially unresectable lung cancer.

Salvage surgery for primary lung cancer is expected to become increasingly common. This study aimed to clarify the survival impact of pathologic characteristics after salvage surgery. Consecutive patients who underwent salvage surgery following definitive chemoradiotherapy or systemic therapy for initially unresectable lung cancer from 2010 to 2020 were enrolled in this study. The tumor slides were reviewed to determine the size of the tumor bed and the proportions of viable tumor, necrosis, and stroma. A total of 23 patients were evaluated, and 18 had clinical stage IIIB-IV disease. Six received chemoradiotherapy and 17 received systemic therapy alone. A major pathologic response (MPR, ≤ 10% of viable tumor) was observed in 6 patients, and 4 patients achieved a pathological complete response. The 3-year overall and recurrence-free survival rates (OS and RFS) were 78.6% and 59.2%, respectively. There was no significant difference in OS between patients with and without MPR, and even non-MPR patients achieved a favorable 3-year OS of 70.2%. Meanwhile, patients with high (≥ 30%) stroma showed significantly better OS than those with low (< 30%) stroma (3-year OS: 100% vs. 23.3%, p < 0.001). This study showed that the proportion of stroma can be useful for predicting long-term survival after salvage surgery. Further large-scale studies are warranted to confirm the current findings.

SIMAP500: A novel risk score to identify recipients at higher risk of hepatocellular carcinoma recurrence following liver transplantation.

Recurrence of hepatocellular carcinoma (HCC) following liver transplantation (LT) has a devastating influence on recipients' survival; however, the risk of recurrence is not routinely stratified. Risk stratification is vital with a long LT waiting time, as that could influence the recurrence despite strict listing criteria. This study aims to identify predictors of recurrence and develop a novel risk prediction score to forecast HCC recurrence following LT. A retrospective review of LT for HCC recipients at University Hospitals Birmingham between July 2011 and February 2020. Univariate and multivariate analyses were performed to identify recurrence predictors, based on which the novel SIMAP500 (satellite nodules, increase in size, microvascular invasion, AFP > 500, poor differentiation) risk score was proposed. 234 LTs for HCC were performed with a median follow-up of 5.3 years. Recurrence developed in 25 patients (10.7%). On univariate analyses, RETREAT score > 3, α-fetoprotein (AFP) at listing 100-500 and > 500, bridging, increased tumour size between imaging at the listing time and explant histology, increase in the size of viable tumour between listing and explant, presence of satellite nodules, micro- and macrovascular invasion on explant and poor differentiation of tumours were significantly associated with recurrence, based on which, the SIMAP500 risk score is proposed. The SIMAP500 demonstrated an excellent predictive ability (c-index = 0.803) and outperformed the RETREAT score (c-index = 0.73). SIMAP500 is indicative of the time to disease recurrence. SIMAP500 risk score identifies the LT recipients at risk of HCC recurrence. Risk stratification allows patient-centric post-transplant surveillance programs. Further validation of the score is recommended.

Neoadjuvant nivolumab or nivolumab plus ipilimumab in early-stage triple-negative breast cancer: a phase 2 adaptive trial

Immune checkpoint inhibition (ICI) with chemotherapy is now the standard of care for stage II–III triple-negative breast cancer; however, it is largely unknown for which patients ICI without chemotherapy could be an option and what the benefit of combination ICI could be. The adaptive BELLINI trial explored whether short combination ICI induces immune activation (primary end point, twofold increase in CD8+ T cells or IFNG), providing a rationale for neoadjuvant ICI without chemotherapy. Here, in window-of-opportunity cohorts A (4 weeks of anti-PD-1) and B (4 weeks of anti-PD-1 + anti-CTLA4), we observed immune activation in 53% (8 of 15) and 60% (9 of 15) of patients, respectively. High levels of tumor-infiltrating lymphocytes correlated with response. Single-cell RNA sequencing revealed that higher pretreatment tumor-reactive CD8+ T cells, follicular helper T cells and shorter distances between tumor and CD8+ T cells correlated with response. Higher levels of regulatory T cells after treatment were associated with nonresponse. Based on these data, we opened cohort C for patients with high levels of tumor-infiltrating lymphocytes (≥50%) who received 6 weeks of neoadjuvant anti-PD-1 + anti-CTLA4 followed by surgery (primary end point, pathological complete response). Overall, 53% (8 of 15) of patients had a major pathological response (<10% viable tumor) at resection, with 33% (5 of 15) having a pathological complete response. All cohorts met Simon’s two-stage threshold for expansion to stage II. We observed grade ≥3 adverse events for 17% of patients and a high rate (57%) of immune-mediated endocrinopathies. In conclusion, neoadjuvant immunotherapy without chemotherapy demonstrates potential efficacy and warrants further investigation in patients with early triple-negative breast cancer. ClinicalTrials.gov registration: NCT03815890.

Neoadjuvant nivolumab and relatlimab in locally advanced MMR-deficient colon cancer: a phase 2 trial

Mismatch repair deficiency (dMMR) is found in approximately 15% of non-metastatic colon cancers (CCs) and is characterized by a defective DNA mismatch repair system, resulting in hypermutated and highly immunogenic tumors. Although patients with dMMR CC have limited benefit from chemotherapy, these tumors have been shown to respond exceptionally well to neoadjuvant anti-PD-1 plus anti-CTLA-4, with high rates of pathologic responses. Here, based on data from melanoma studies, we postulated a high efficacy and favorable toxicity profile of anti-PD-1 plus anti-LAG-3. In the NICHE-3 study, a total of 59 patients with locally advanced dMMR CC were treated with two 4-weekly cycles of nivolumab (480 mg) plus relatlimab (480 mg) before surgery. Pathologic response was observed in 57 of 59 (97%; 95% confidence interval (CI): 88–100%) patients, meeting the primary endpoint. Responses included 54 (92%; 95% CI: 81–97%) major pathologic responses (≤10% residual viable tumor) and 40 (68%; 95% CI: 54–79%) pathologic complete responses. With a median follow-up of 8 months (range, 2–19), one patient had recurrence of disease. The treatment displayed an acceptable safety profile, with all-grade and grade 3–4 immune-related adverse events (irAEs) occurring in 80% and 10% of patients, respectively. The most common irAEs were infusion-related reactions (29%), thyroid dysfunction (22%) and fatigue (20%). In conclusion, our results show that neoadjuvant nivolumab/relatlimab induces high rates of pathologic responses and that further investigation of this treatment in larger studies is warranted. These data add to the body of evidence in support of neoadjuvant immunotherapy regimens in dMMR CC. ClinicalTrials.gov identifier: NCT03026140.

A bioengineered tumor matrix-based scaffold for the evaluation of melatonin efficacy on head and neck squamous cancer stem cells

Head and neck squamous cell carcinoma (HNSCC) presents a significant challenge worldwide due to its aggressiveness and high recurrence rates post-treatment, often linked to cancer stem cells (CSCs). Melatonin shows promise as a potent tumor suppressor; however, the effects of melatonin on CSCs remain unclear, and the development of models that closely resemble tumor heterogeneity could help to better understand the effects of this molecule. This study developed a tumor scaffold based on patient fibroblast-derived decellularized extracellular matrix that mimics the HNSCC microenvironment. Our study investigates the antitumoral effects of melatonin within this context. We validated its strong antiproliferative effect on HNSCC CSCs and the reduction of tumor invasion and migration markers, even in a strongly chemoprotective environment, as it is required to increase the minimum doses necessary to impact tumor viability compared to the non-scaffolded tumorspheres culture. Moreover, melatonin exhibited no cytotoxic effects on healthy cells co-cultured in the tumor hydrogel. This scaffold-based platform allows an in vitro study closer to HNSCC tumor reality, including CSCs, stromal component, and a biomimetic matrix, providing a new valuable research tool in precision oncology.

Turkish coffee has an antitumor effect on breast cancer cells in vitro and in vivo

BackgroundBreast cancer is the most diagnosed cancer in women. Its pathogenesis includes several pathways in cancer proliferation, apoptosis, and metastasis. Some clinical data have indicated the association between coffee consumption and decreased cancer risk. However, little data is available on the effect of coffee on breast cancer cells in vitro and in vivo.MethodsIn our study, we assessed the effect of Turkish coffee and Fridamycin-H on different pathways in breast cancer, including apoptosis, proliferation, and oxidative stress. A human breast cancer cell line (MCF-7) was treated for 48 h with either coffee extract (5% or 10 v/v) or Fridamycin-H (10 ng/ml). Ehrlich solid tumors were induced in mice for in vivo modeling of breast cancer. Mice with Ehrlich solid tumors were treated orally with coffee extract in drinking water at a final concentration (v/v) of either 3%, 5%, or 10% daily for 21 days. Protein expression levels of Caspase-8 were determined in both in vitro and in vivo models using ELISA assay. Moreover, P-glycoprotein and peroxisome proliferator-activated receptor gamma (PPAR-γ) protein expression levels were analyzed in the in vitro model. β-catenin protein expression was analyzed in tumor sections using immunohistochemical analysis. In addition, malondialdehyde (MDA) serum levels were analyzed using colorimetry.ResultsBoth coffee extract and Fridamycin-H significantly increased Caspase-8, P-glycoprotein, and PPAR-γ protein levels in MCF-7 cells. Consistently, all doses of in vivo coffee treatment induced a significant increase in Caspase-8 and necrotic zones and a significant decrease in β- catenin, MDA, tumor volume, tumor weight, and viable tumor cell density.ConclusionThese findings suggest that coffee extract and Fridamycin-H warrant further exploration as potential therapies for breast cancer.

Detection of bone cancer based on a four-phase framework generative deep belief neural network in deep learning

The medical image processing plays an important role in analyzing and detecting tumors and detecting cancer cells in their early stages. Microscopic images were used as a deep learning approach to recognize bone features. These images were acquired using microscopy, a time-consuming and labor-intensive process that required repeating. Cancer cells cannot be identified by conventional techniques because of the noise in the images. To address these challenges, this paper introduces the Gated Convolutional Neural Network (GCNN) techniques used to identify multiclass bone cancer, including non-tumor, non-viable, and viable tumors. As a first stage, the most basic part of image Preprocessing is to deposing without interrupting the diagnostics information during the removal of noise. The second stage is edge detection, used for image brightness discontinuity detection based on Scaled Region Edge Detector (SRED). It is used for image segmentation and data extraction within regions based on the Screen Cluster Area Segmentation (SCAS) to segment the Region of Interest (RoI) based on Relative Scalar Color Histogram (RSCH). The fourth step is Feature extraction is to find out the features and match the image feature from the Bone Cancer Detection object based on the maximum threshold weights using GCNN with Maximum Standard External Regions (MSER) used for features extracting applied to improve feature quality analysis and Feature support rate. This results in higher classification accuracy, Precision, recall under F-measure, and lower error rates. This enables a more achieved classification than other existing methods.

Histological Assessment and Interobserver Agreement in Major Pathologic Response for Non-Small Cell Lung Cancer with Neoadjuvant Therapy.

Major pathologic response (MPR), defined as ≤10% of residual viable tumor (VT), is a prognostic factor in non-small cell lung cancer (NSCLC) after neoadjuvant therapy. This study evaluated interobserver reproducibility in assessing MPR, compared area-weighted and unweighted VT (%) calculation, and determined optimal VT (%) cutoffs across histologic subtypes for survival prediction. This retrospective study included 108 patients with NSCLC who underwent surgical resection after neoadjuvant chemotherapy or chemoradiation at Seoul National University Bundang Hospital between 2009-2018. Three observers with varying expertise independently assessed tumor bed and VT (%) based on digital whole-slide images. Reproducibility in tumor bed delineation was reduced in squamous cell carcinoma (SqCC) with smaller tumor bed, although overall concordance was high (Dice coefficient, 0.96; IoU score, 0.92). Excellent agreement was achieved for VT (%) (ICC=0.959) and MPR using 10% cutoff (Fleiss' kappa=0.911). Shifting between area-weighted and unweighted VT (%) showed only one case differing in MPR status out of 81 cases. The optimal cutoff was 10% for both adenocarcinoma (ADC) and SqCC. MPR+ was observed in 18 patients (17%), with SqCC showing higher MPR+ rates (p=0.044), lower VT (%) (p<0.001), and better event-free survival (p=0.015) than ADC. MPR+ significantly improved overall survival (p=0.023), event-free survival (p=0.001), and lung cancer-specific survival (p=0.012). While MPR assessment demonstrated robust reproducibility with minimal impact from the tumor bed, attention is warranted when evaluating smaller tumor beds in SqCC. A 10% cutoff reliably predicted survival across histologic subtypes with higher interobserver reproducibility.

Single-Atom Ce-Doped Metal Hydrides with High Phosphatase-like Activity Amplify Oxidative Stress-Induced Tumor Apoptosis.

Phosphates within tumors function as key biomolecules, playing a significant role in sustaining the viability of tumors. To disturb the homeostasis of cancer cells, regulating phosphate within the organism proves to be an effective strategy. Herein, we report single-atom Ce-doped Pt hydrides (Ce/Pt-H) with high phosphatase-like activity for phosphate hydrolysis. The resultant Ce/Pt-H exhibits a 26.90- and 6.25-fold increase in phosphatase-like activity in comparison to Ce/Pt and Pt-H, respectively. Mechanism investigations elucidate that the Ce Lewis acid site facilitates the coordination with phosphate groups, while the surface hydrides enhance the electron density of Pt for promoting catalytic ability in H2O cleavage and subsequent nucleophilic attack of hydroxyl groups. Finally, by leveraging its phosphatase-like activity, Ce/Pt-H can effectively regulate intracellular phosphates to disrupt redox homeostasis and amplify oxidative stress within cancer cells, ultimately leading to tumor apoptosis. This work provides fresh insights into noble-metal-based phosphatase mimics for inducing tumor apoptosis.

In Vivo Detection of Multidrug-Resistance Related Proteins in Locally Advanced Breast Cancer Using 99mTc-MIBI SPECT/CT Imaging: Correlation with Clinical Outcomes.

Neoadjuvant chemotherapy (NACT) is widely used for treating locally advanced Breast cancer (LABC). However, development of multidrug resistance (MDR) is the main underlying factor for chemoresistance. Technetium-99m methoxyisobutylisonitrile (99mTc-MIBI) is a substrate for MDR. This study aimed to analyze the relationship between expression of MDR-related proteins (P-gp and Bcl-2) and 99mTc-MIBI uptake and retention in BC tumor cells, pathologic response to NACT, disease free survival (DFS) and overall survival (OS). prospective analysis recruited 31 patients with LABC who received NACT between January 2019 and March 2020. 99mTc-MIBI planar and SPECT/CT imaging was conducted before and after NACT. Qualitative and quantitative analyses were performed, pre and post-NACT early and delayed lesion to non-lesion (LNL) ratios, and retention index (RI) of 99mTc-MIBI were calculated. Expression of P-gp and Bcl-2 in tumor cells was determined by immunohistochemistry. Quantitively, inter-reader ICC for SPECT/CT based quantification was consistently higher than that of planar images. Post-NACT LNL ratios were significantly higher in patients with pathologic persistent disease (PPD). A change in RI between pre- and post-NACT scans demonstrated a significant association with DFS with a hazard ratio of 0.7 (95%CI: 06-1.0). Qualitatively, SPECT/CT was significantly more accurate compared to planar imaging in identifying residual viable tumor (81% compared to 57%). Her2neu positivity and high post-operative Bcl-2 and P-gp were associated with worse DFS. A significant association was found between increased expression of post-NACT Bcl-2 and PPD, advanced tumor stage and poor OS. 99mTc-MIBI SPECT/CT based qualitative evaluation of BC response to NACT is more accurate than planar imaging. Post-NACT MIBI retention is positively correlated with P-gp and Bcl-2 expression. 99mTc-MIBI SPECT/CT may predict MDR development. High post-NACT Bcl-2 expression is significantly associated with advanced tumor stage and OS. High post-NACT P-gp expression has a worse impact on pathologic response and DFS.

EWS-WT1 fusion isoforms establish oncogenic programs and therapeutic vulnerabilities in desmoplastic small round cell tumors

EWS fusion oncoproteins underlie several human malignancies including Desmoplastic Small Round Cell Tumor (DSRCT), an aggressive cancer driven by EWS-WT1 fusion proteins. Here we combine chromatin occupancy and 3D profiles to identify EWS-WT1-dependent gene regulation networks and target genes. We show that EWS-WT1 is a powerful chromatin activator controlling an oncogenic gene expression program that characterizes primary tumors. Similar to wild type WT1, EWS-WT1 has two isoforms that differ in their DNA binding domain and we find that they have distinct DNA binding profiles and are both required to generate viable tumors that resemble primary DSRCT. Finally, we identify candidate EWS-WT1 target genes with potential therapeutic implications, including CCND1, whose inhibition by the clinically-approved drug Palbociclib leads to marked tumor burden decrease in DSRCT PDXs in vivo. Taken together, our studies identify gene regulation programs and therapeutic vulnerabilities in DSRCT and provide a mechanistic understanding of the complex oncogenic activity of EWS-WT1.

Pathologic complete response following neoadjuvant chemotherapy in pancreatic ductal adenocarcinoma: Impact on survival and recurrence

BackgroundPathologic complete response after neoadjuvant treatment in pancreatic ductal adenocarcinoma is a rare occurrence. Similar to other malignancies, achieving a pathologic complete response in pancreatic ductal adenocarcinoma seems to correlate with improved survival. However, because of the rarity of such events, the true significance of pathologic complete response in pancreatic cancer remains unclear. The aim of the present study was to investigate the impact of pathologic complete response on survival and recurrence. MethodsIn a single-center retrospective study, pathologic complete response was defined as no evidence of viable tumor cells in resected specimen entirely sampled according to a rigorous protocol and in which a residual tumor bed was identified. Disease-specific survival and disease-free survival were measured from surgery. Independent predictors for disease-specific survival and disease-free survival were examined. ResultsOverall, 403 patients were included. Pathologic complete response was found in 15 patients (3.8%), after chemotherapy alone. After a median follow-up of 42 months (95% CI 38–45), 3-year disease-specific survival was 87% in pathologic complete response patients vs 43% in those without pathologic complete response (P = .014). The recurrence rate was 40% (n = 6/15) in the pathologic complete response group compared with 69.8% (n = 271/388) in those without pathologic complete response. Disease-free survival was longer in the pathologic complete response group, with higher 1- and 3-year rates compared with the no–pathologic complete response group (80% vs 60% and 48% vs 24%, respectively). Pathologic complete response was found to be an independent protective factor for disease-specific survival (P = .035) but not for disease-free survival (P = .052). ConclusionPathologic complete response in pancreatic ductal adenocarcinoma is not synonymous of cure but ensure a prolonged survival. Nevertheless, recurrence remains a significant concern, with high rates observed even among these exceptional responders.