Search Results (61)

Purpose: Neoadjuvant endocrine therapy (NET) represents a valuable treatment option for hormone receptor-positive (HR+)/HER2-negative breast cancer, particularly in postmenopausal women. This study aimed to evaluate the clinical and histopathological efficacy of NET and to explore early and late changes in Ki-67 and progesterone receptor (PgR) expression as indicators of endocrine response. Methods: A prospective cohort of 127 postmenopausal patients with stage cT1–4N0–3M0 HR+/HER2− breast cancer was enrolled between 2019 and 2021. Patients received NET (mostly letrozole) for a mean of 7.7 months. In 80 cases, a second core biopsy was performed after four weeks. Tumor size, histological grade, and biomarkers (Ki-67, PgR) were assessed pre- and post-treatment. Results: NET led to a significant reduction in tumor size, with median shrinkage of 47.0% (from 32.0 mm to 17.0 mm, p < 0.0001). Breast-conserving surgery (BCS) was performed in 52.2% of patients and lymph node negativity (pN0) was observed in 50.4%. Median Ki-67 decreased from 20.0% at baseline to 5.0% after four weeks (p < 0.0001) and remained low in surgical specimens (median 5.0%, p < 0.0001). In 33.3% of patients, Ki-67 dropped below 2.7%, and 67.0% showed a concordant decrease in both Ki-67 and PgR. PgR expression declined significantly during treatment (p < 0.0001). HER2 status conversion was noted in 6.4% of patients during treatment. Pathological complete response (pCR) occurred in 3.5%, while minimal or moderate residual disease (RCB I–II) was identified in 71.3% of cases. Conclusions: NET effectively reduced tumor burden and histological aggressiveness, enabling higher rates of BCS. Early reduction in Ki-67 and PgR may serve as surrogate markers of endocrine responsiveness, supporting their use for treatment stratification and monitoring during NET in HR+/HER2− breast cancer. Full article

Objectives: Inflammation plays an important role in cancer development, and various inflammation parameters are used as potential prognostic markers. This study aimed to evaluate the effectiveness of the combined use of HALP and H index in predicting pathological response to neoadjuvant therapy in patients with HER2-positive early-stage breast cancer. Method: This retrospective cohort study was conducted on 146 HER2-positive breast cancer patients treated in two centers. To stratify patients by their predicted probability of pathological response, HALP and H index values were combined into a composite biomarker score called the combined response score (CRS). Patients were classified into three groups based on biomarker levels: 0 = low CRS (low predictive score), 1 = intermediate CRS, and 2 = high CRS (high predictive score). These groups reflect predicted response likelihood and do not represent actual pathological outcomes. Pathological response results were evaluated according to the combined response score. Pathological complete response (pCR) was defined as residual cancer burden (RCB) 0, indicating no residual invasive tumor in breast or lymph nodes. Results: The mean age of 146 early-stage breast cancer patients included in our study was 52.3 ± 11.3 (min: 29-max: 83). In the ROC analysis, the optimum cut-off value for the HALP score in pathological response classification was found to be 36 (AUC = 0.608, sensitivity = 76.29%, specificity = 44.9%, PPV = 73%, NPV = 47.89%) and 2.3 for the H index (AUC = 0.641, sensitivity = 65.98%, specificity = 51.02%, PPV = 72.73%, NPV = 43.1%). While the pathological complete response rate was 66.4% in all patients, it was 81.8% in those with a combined score of 2, 51% in those with a score of 1, and 58.6% in those with a score of 0 (p < 0.001). In the logistic regression analysis, the probability of pathological response in patients in the combined score = 2 group is 3.77 times higher than in group 0. In the Fagan nomogram, the pretest probability of pathological response is 66%, while the post-test probability for combined response score group 2 is 81.5%, and for the low-H index < 2.3 and the high-HALP ≥ 36 patient group, our estimate for pathological complete response increases to 82%. Conclusions: The HALP-H index combined score is an important predictor of pathological response in early-stage HER2-positive breast cancer patients, independent of histological type and stage. This new score may enable personalized approaches in treatment planning. Full article

Background: The role of neoadjuvant endocrine therapy (NET) in patients with luminal tumors is still not well defined in everyday clinical practice. To assess the efficacy of combination NET, we analyzed the outcomes of fulvestrant and aromatase inhibitors (AI) in combination in a real-world population. Methods: This was a single-arm, retrospective longitudinal study of the total population of patients diagnosed with locoregionally advanced, clinical stage II-III, HR+ HER2-, luminal-type eBC, who were treated with the neoadjuvant combination of fulvestrant and AI between 2019 and 2024 at the Clinical University Hospital of Split, Croatia. Results: We enrolled 44 patients in the intention-to-treat (ITT) population, while 34 completed NET and surgery (per-protocol population; PPP). The median duration of NET was 11 months (interquartile range [IQR] of 9–16 months). The best radiological objective response rate (partial or complete response) was achieved by 30 (68.2%) in ITT, and 26 (76.5%) in PPP, defined by radiological examination, breast ultrasound, or MR. In the PPP, the minimal or moderate pathological response according to residual cancer burden (I or II) was observed in 29 (85.3%) patients. The median of absolute changes in Ki-67 was −5 (95% CI: −9 to 0), and the median of relative Ki67 changes was −40% (95% CI: −72% to 0%). Post-surgical Ki-67 was significantly predicted by initial Ki-67, positive lymph nodes, and time from diagnosis to the initiation of NET. Treatment was well tolerated, with no therapy discontinuation or dose reductions needed due to toxicity. The most commonly reported side effects included musculoskeletal pain (45.5%), asthenia (34.1%), and hot flashes (29.5%). Conclusions: Dual hormonal therapy with fulvestrant and AI is an active, easily given, non-toxic, promising neoadjuvant treatment in real-world patients with locally advanced luminal-type eBC who are not candidates for chemotherapy. Full article

Muscle-invasive bladder cancer (MIBC) is a biologically aggressive disease with high recurrence rates, despite advances in surgical and systemic therapies. Circulating tumor DNA (ctDNA), a tumor-specific fraction of cell-free DNA, has emerged as a promising non-invasive biomarker for the real-time assessment of tumor burden, treatment response, and minimal residual disease (MRD). This review explores the biological basis, detection technologies, and clinical utility of ctDNA in MIBC, highlighting its role in preoperative risk stratification, postoperative surveillance, and personalized decision-making for adjuvant and systemic therapies. We critically examine current evidence from pivotal trials and ongoing studies that support ctDNA’s prognostic and predictive value. Additionally, we discuss emerging applications, including ctDNA-guided immunotherapy, integration with imaging and molecular data, and potential to inform bladder-sparing strategies. While ctDNA presents technical and logistical challenges, its incorporation into prospective clinical workflows promises to enhance precision oncology and improve outcomes in patients with MIBC. Full article

Colorectal cancer (CRC) remains a major health burden in Japan, with precision medicine playing an increasingly critical role in treatment optimization. Key biomarkers, including RAS, BRAF, microsatellite instability/mismatch repair, and human epidermal growth factor receptor 2, can be used as a guide for molecularly targeted therapies and immunotherapy. Advances in molecular diagnostics, including comprehensive genomic profiling, have enabled more precise treatment selection such as RET and NTRK fusions. Nationwide initiatives, such as c-CAT and SCRUM-Japan, can leverage real-world data to refine clinical strategies. Recent developments in circulating tumor DNA analysis have led to novel approaches for minimal residual disease monitoring, as demonstrated by the CIRCULATE-Japan GALAXY study. However, certain challenges persist, including the time required for genetic testing, the limited availability of targeted therapies, and disparities in access to molecular tumor boards. This review summarizes the current landscape of precision medicine in CRC in Japan, emphasizing key biomarkers, genetic testing strategies, targeted therapies, and emerging technologies. Future research should focus on expanding clinical trial access, accelerating drug approvals, and integrating real-world data into clinical practice to further advance precision medicine. Full article

Background: Neoadjuvant therapy (NAT) plays a crucial role in breast cancer (BC) management by enabling tumor and nodal downstaging. While axillary lymph node dissection (ALND) remains the standard for patients with residual nodal disease after NAT, its prognostic benefit is debated. Identifying predictors of high-burden residual axillary disease may guide treatment intensification and surgical de-escalation strategies. Methods: We retrospectively analyzed 262 BC patients treated with NAT followed by ALND between 2006 and 2023. Patients were stratified into low- (ypN0-mi-1) and high-burden (ypN2-3) residual axillary disease groups. Univariate and multivariate logistic regression analyses were performed to identify independent predictors of high-burden residual disease. Results: High-burden residual axillary disease was observed in 35.9% of patients. Baseline cN+ status (OR = 7.697, p = 0.013), HR+/HER2− subtype (OR = 3.945, p = 0.003), and larger post-NAT tumor size (OR = 1.043, p < 0.001) were independent predictors. Conclusions: Identifying patients at risk of high-burden residual axillary disease is essential to optimize neoadjuvant strategies. Increasing axillary pathological complete response may reduce the need for ALND, minimizing surgical morbidity without compromising oncological outcomes. Full article

(1) Background: GEP-NETs are frequently diagnosed at advanced stage. For well-differentiated somatostatin receptor-positive (SSTR+) NETs, SSA are the preferred first-line therapy. However, in newly diagnosed patients with G2/G3 and a high tumor burden, SSA alone might not be enough; (2) Methods: We conducted a retrospective analysis to assess the effectiveness of combining oxaliplatin–fluoropyrimidine chemotherapy with SSA as an upfront strategy in newly diagnosed metastatic G2/G3 GEP-NET patients treated with oxaliplatin–fluoropyrimidine-based chemotherapy; (3) Results: Between March 2017 and October 2023, 32 pts (19 males, 13 females; M:F = 1.5:1; median age 54 years, range 31–82) were deemed eligible to receive oxaliplatin–fluoropyrimidine chemotherapy in addition to SSA; 14 received XELOX and 18 FOLFOX. After a median follow-up of 26 mo., each patient had completed at least two cycles of chemotherapy. The ORR was 25%, with a median DoR of 21.3 mo. The DCR was 87.5%. Notably, 28.1% of patients experienced tumor shrinkage sufficient for radical surgery on residual tumor lesions, encompassing both primary tumors and metastases; (4) Conclusions: Upfront treatment with the combination of oxaliplatin–fluoropyrimidine and SSA demonstrated effectiveness and safety. This approach may be considered to facilitate conversion surgery in eligible patients. Full article

Background: Wilms’ tumor gene 1 (WT1) is a critical player in acute myeloid leukemia (AML), often serving as a biomarker for measurable residual disease (MRD). The WT1 gene is overexpressed in the majority of AML cases at diagnosis, with apparently no correlation with prognosis, and in the meantime, its role in patients with low-level expression is still undefined. This study investigates the mutational landscape and clinical outcomes of AML patients with low WT1 expression at diagnosis. Methods: We analyzed 34 AML patients with low WT1 expression (WT1/ABL1 < 250) diagnosed and treated from 2013 to 2017 at three institutions. Next-generation sequencing (NGS) was employed to investigate the mutational status of 32 genes commonly mutated in AML. The presence of specific mutations, as well as clinical outcomes, was compared to the general AML population. Results: Patients with low WT1 expression showed a significantly higher mutational burden, with a median of 3.4 mutations per patient, compared to the general AML population. Notably, clonal hematopoiesis (CHIP) or myelodysplasia-related (MR) mutations, particularly in ASXL1, TET2, and SRSF2, were present in most patients with low WT1 expression. All but one case of NPM1- or FLT3-mutant AML in the low-WT1 cohort harbored more CHIP or MR mutations. Patients with low WT1 expression had an overall survival (OS) that was superimposable to the OS expected in MR AML. Conclusions: Low WT1 expression in AML is associated with a distinct and complex mutational profile, marked by frequent CHIP and MR mutations. Full article

Colorectal cancer (CRC) represents a heterogeneous group of diseases that imposes a considerable global and national health burden. Although most CRC patients are diagnosed at an early stage and undergo potentially curative treatment, a significant proportion experience recurrence. Currently, adjuvant chemotherapy decisions are primarily based on clinicopathological characteristics, which have well-recognized limitations in accurately identifying patients harboring minimal residual disease (MRD), often resulting in unnecessary chemotherapy exposure. Circulating tumor DNA (ctDNA) has emerged as a promising surrogate marker for MRD, offering a more precise approach to identifying patients at risk of recurrence after curative-intent surgery and refining adjuvant chemotherapy decisions. Growing evidence from multiple studies has demonstrated that ctDNA outperforms traditional clinicopathological factors as a marker for MRD. This review synthesizes key studies supporting the role of ctDNA in MRD detection for CRC patients and evaluates clinical trials investigating the application of ctDNA in guiding adjuvant therapy decisions. This emerging strategy holds the potential to transform the adjuvant treatment paradigm in colorectal cancer by optimizing therapeutic precision and minimizing unnecessary treatment. Full article

Eumycetoma, a chronic fungal infection caused by Madurella mycetomatis, is a neglected tropical disease characterized by tumor-like growths that can lead to permanent disability and deformities if untreated. Predominantly affecting regions in Africa, South America, and Asia, it imposes significant physical, social, and economic burdens. Current treatments, including antifungal drugs like itraconazole, often show variable efficacy, with severe cases necessitating surgical intervention or amputation. Drug discovery for eumycetoma faces challenges due to limited understanding of the disease’s molecular mechanisms and the lack of 3D structures for key targets such as Madurella mycetomatis CYP51, a well-known target for azoles’ antifungal agents. To address these challenges, this study employed computational approaches, including homology modeling, virtual screening, free energy calculations, and molecular dynamics simulations, to repurpose FDA-approved drugs as potential treatments for eumycetoma targeting Madurella mycetomatis CYP51. To this end, a library of 2619 FDA-approved drugs was screened, identifying three promising candidates: montelukast, vilanterol, and lidoflazine. These compounds demonstrated favorable binding affinities, strong interactions with critical residues of the homology model of Madurella mycetomatis CYP51, and stability in molecular dynamics simulations, offering potential for further investigation as effective therapeutic options for eumycetoma. Full article

Background: In infant KMT2A (MLL1)-rearranged (MLL-r) acute lymphoblastic leukemia (ALL), early relapse and treatment response are currently monitored through invasive repeated bone marrow (BM) biopsies. Circulating tumor DNA (ctDNA) in peripheral blood (PB) provides a minimally invasive alternative, allowing for more frequent disease monitoring. However, a poor understanding of ctDNA dynamics has hampered its clinical translation. We explored the predictive value of ctDNA for detecting minimal/measurable residual disease (MRD) and drug response in a patient-derived xenograft (PDX) model of infant MLL-r ALL. Methods: Immune-deficient mice engrafted with three MLL-r ALL PDXs were monitored for ctDNA levels before and after treatment with the menin inhibitor SNDX-50469. Results: The amount of ctDNA detected strongly correlated with leukemia burden during initial engraftment prior to drug treatment. However, following SNDX-50469 treatment, the leukemic burden assessed by either PB leukemia cells through flow cytometry or ctDNA levels through droplet digital polymerase chain reaction (ddPCR) was discrepant. This divergence could be attributed to the persistence of leukemia cells in the spleen and BM, highlighting the ability of ctDNA to reflect disease dynamics in key leukemia infiltration sites. Conclusions: Notably, ctDNA analysis proved to be a superior predictor of MRD compared to PB assessment alone, especially in instances of low disease burden. These findings highlight the potential of ctDNA as a sensitive biomarker for monitoring treatment response and detecting MRD in infant MLL-r ALL. Full article

Background: This study aims to deliver more insights on the impact of neoadjuvant treatment on Pd-L1 expression and to evaluate its correlation with clinicopathological factors. Methods: We reviewed 88 TNBC cases for the period 2021–2023. Data on age, tumor size, stage, and treatment were collected. Histological slides were assessed for subtype, grade, and TILs. A total of 48 received neoadjuvant treatment. HER2 and Ki67 were evaluated via immunohistochemistry. PD-L1 expression was tested on primary and residual tumors. Statistical analysis was performed using IBM SPSS (p < 0.05). Results: In this study, PD-L1 positive expression was found in 44.3% of primary tumors, with 52.9% of initially positive cases losing expression post-treatment. TILs were significantly higher in PD-L1-positive tumors (mean 41.79% vs. 27.55%, p = 0.001). A notable correlation was found between PD-L1 expression and Ki-67 proliferation index, with PD-L1-positive tumors having a median Ki-67 of 64.49 compared to 52.86 in negative cases (p = 0.015). Neoadjuvant immunotherapy led to a lower mean residual cancer burden (0.95 vs. 2.55, p = 0.002) compared to chemotherapy alone. Higher Ki-67 levels (≥50%) were associated with better treatment outcomes, showing a mean RCB score of 1.60 versus 3.16 for lower levels (p = 0.022). HER2-negative cases had a higher prevalence of favorable pathological response (54.5%) compared to HER2-low tumors (25%, p = 0.048), because of the strong correlation to high proliferative index. Conclusions: In conclusion, PD-L1 expression in TNBC shows significant discordance post-treatment, highlighting the need for routine testing and further research on predictive biomarkers. Full article

Background: This multicenter and retrospective study investigated the additive value of tumor morphologic features derived from the functional tumor volume (FTV) tumor mask at pre-treatment (T0) and the early treatment time point (T1) in the prediction of pathologic outcomes for breast cancer patients undergoing neoadjuvant chemotherapy. Methods: A total of 910 patients enrolled in the multicenter I-SPY 2 trial were included. FTV and tumor morphologic features were calculated from the dynamic contrast-enhanced (DCE) MRI. A poor response was defined as a residual cancer burden (RCB) class III (RCB-III) at surgical excision. The area under the receiver operating characteristic curve (AUC) was used to evaluate the predictive performance. The analysis was performed in the full cohort and in individual sub-cohorts stratified by hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) status. Results: In the full cohort, the AUCs for the use of the FTV ratio and clinicopathologic data were 0.64 ± 0.03 (mean ± SD [standard deviation]). With morphologic features, the AUC increased significantly to 0.76 ± 0.04 (p < 0.001). The ratio of the surface area to volume ratio between T0 and T1 was found to be the most contributing feature. All top contributing features were from T1. An improvement was also observed in the HR+/HER2- and triple-negative sub-cohorts. The AUC increased significantly from 0.56 ± 0.05 to 0.70 ± 0.06 (p < 0.001) and from 0.65 ± 0.06 to 0.73 ± 0.06 (p < 0.001), respectively, when adding morphologic features. Conclusion: Tumor morphologic features can improve the prediction of RCB-III compared to using FTV only at the early treatment time point. Full article

Neoadjuvant chemotherapy (NAC) is now the standard of care for patients with locally advanced breast cancer (BC). TIL scoring is prognostic and adds predictive value to the residual cancer burden evaluation after NAC. However, NAC induces changes in the tumor, and the reliability of TIL scoring in post-NAC samples has not yet been studied. H&E- and dual CD3/CD20 chromogenic IHC-stained tissues were scored for stromal and intra-tumoral TIL by two experienced pathologists on pre- and post-treatment BC tissues. Digital TIL scoring was performed using the HALO^® image analysis software (version 2.2). In patients with residual disease, we show a good inter-pathologist correlation for stromal TIL on H&E-stained tissues (CCC value 0.73). A good correlation for scoring with both staining methods (CCC 0.81) and the digital TIL scoring (CCC 0.77) was also observed. Overall concordance for TIL scoring in patients with a complete response was however poor. This study reveals there is good reliability for TIL scoring in patients with detectable residual tumors after NAC treatment, which is comparable to the scoring of untreated breast cancer patients. Based on the good consistency observed with digital TIL scoring, the development of a validated algorithm in the future might be advantageous. Full article

The aim of this study was to evaluate outcomes of transarterial radioembolization (TARE) for hepatocellular carcinoma (HCC) in patients previously treated with transarterial embolization (TAE). In this retrospective study, all HCC patients who received TARE from 1/2012 to 12/2022 for treatment of residual or recurrent disease after TAE were identified. Overall survival (OS) was estimated using the Kaplan–Meier method. Univariate Cox regression was performed to determine significant predictors of OS after TARE. Twenty-one patients (median age 73.4 years, 18 male, 3 female) were included. Median dose to the perfused liver volume was 121 Gy (112–444, range), and 18/21 (85.7%) patients received 112–140 Gy. Median OS from time of HCC diagnosis was 32.9 months (19.4–61.4, 95% CI). Median OS after first TAE was 29.3 months (15.3–58.9, 95% CI). Median OS after first TARE was 10.6 months (6.8–27.0, 95% CI). ECOG performance status of 0 (p = 0.038), index tumor diameter < 4 cm (p = 0.022), and hepatic tumor burden < 25% (p = 0.018) were significant predictors of longer OS after TARE. TARE may provide a survival benefit for appropriately selected patients with HCC who have been previously treated with TAE. Full article