This retrospective, multicenter cohort study aimed to determine whether cancer cachexia serves as a biomarker for determining the most effective treatment for patients having non-small-cell lung cancer (NSCLC) with high programmed death ligand 1 (PD-L1) expression treated with immune checkpoint inhibitors (ICIs) alone or combined with chemotherapy (ICI/chemotherapy). We included 411 patients with advanced NSCLC with a PD-L1 tumor proportion score of ≥50%. The patients were treated with pembrolizumab monotherapy or ICI/chemotherapy. Cancer cachexia was defined as a weight loss of >5% of the total body weight or a body mass index of <20 kg/m2 coupled with an additional weight loss of >2% within 6 months before starting treatment. Eighty-five (21%) patients met the cancer cachexia criteria. Overall survival (OS) was significantly shorter in patients with cachexia than in those without cachexia in both the pembrolizumab monotherapy group (17.2 vs. 35.8 months, p < 0.001) and the ICI/chemotherapy group (27.0 months vs. not reached, p = 0.044). However, after stratifying by cancer cachexia status, no significant difference in OS was observed between the pembrolizumab monotherapy and chemoimmunotherapy groups, regardless of cachexia. In conclusion, ICI/chemotherapy offers limited benefits for NSCLC patients with high PD-L1 expression and concurrent cancer cachexia. Considering the frailty associated with cachexia, ICI monotherapy may be preferred to ICI/chemotherapy for these patients. New interventions that can better address the negative prognostic impact of cachexia in patients treated using ICIs with or without chemotherapy remain warranted.

Immune checkpoint blockers have substantially improved prognosis of melanoma patients, nevertheless, resistance remains a significant problem. Here, intrinsic and extrinsic factors in the tumor microenvironment are discussed, including the expression of alternative immune checkpoints such as lymphocyte activation gene 3 (LAG-3) and T-cell immunoglobulin and mucin domain-containing protein 3 (TIM-3). While most studies focus on immune cell expression of these proteins, we investigated their melanoma cell intrinsic expression by immunohistochemistry in melanoma metastases of 60 patients treated with anti-programmed cell death protein 1 (PD-1) and/or anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) therapy, and correlated it with the expression of potential ligands, RNA sequencing data and clinical outcome. LAG-3 and TIM-3 were commonly expressed in melanoma cells. In the stage IV cohort, expression of LAG-3 was associated with M1 stage (p < 0.001) and previous exposure to immune checkpoint inhibitors (p = 0.029). Moreover, in the anti-PD-1 monotherapy treatment group patients with high LAG-3 expression by tumor cells tended to have a shorter progression-free survival (p = 0.088), whereas high expression of TIM-3 was associated with a significantly longer overall survival (p = 0.007). In conclusion, we provide a systematic analysis of melanoma cell intrinsic LAG-3 and TIM-3 expression, highlighting potential implications of their expression on patient survival.

Venous thromboembolism (VTE) is a frequently encountered paraneoplastic syndrome in patients with ovarian cancer (OC), an inflamm-aging entity. VTE is known to exacerbate their already poor prognosis, which is partially attributed to the contribution of the haemostatic system to ovarian tumourigenesis. In the past decade, numerous single-nucleotide polymorphisms (SNPs) implicated in VTE pathways have been proposed to influence tumour susceptibility and progression. These SNPs represent potential tools to improve the prognosis accuracy of OC patients. Hence, this study explored the influence of 12 haemostasis-associated SNPs on the risk for VTE, risk of OC progression and related death among 98 OC patients. The findings revealed a 20.5 % incidence of VTE, which was associated with more rapid disease progression and shorter survival times (log-rank test, p < 0.05). PROCR rs10747514 (AA/AG vs. GG; odds ratio (OR) = 3.67, p = 0.037) and SERPINE1 rs2070682 (CC/CT vs. TT; OR = 9.28, p = 0.040) were predictors of OC-related VTE development. Regarding patients' prognosis regardless of venous thrombogenesis, RGS7 rs2502448, F3 rs1361600, FGG rs2066865, and SERPINE1 rs2070682 were the most relevant biomarkers in different patient groups. These genetic variants might constitute attractive prognostic indicators among OC patients, offering insights to refine disease management strategies. However, due to the small cohort size and the study's retrospective nature, external validation is necessary to assess the generalisation of the findings.

Diffuse intrinsic pontine glioma (DIPG) carries a poor prognosis with a median survival of less than 12 months. Key molecular features include histone H3 mutation (K27M) and AKT pathway dysregulation. There is currently no curative treatment.

This is a Phase I study of vorinostat and temsirolimus in newly diagnosed (Stratum 1) and progressive (Stratum 2) DIPG (NCT02420613). The primary aims are to determine the safety, maximum tolerated dose (MTD), and toxicities. A modified 3 + 3 design was used to establish the MTD, where the first three patients were assigned the first dose level regardless of stratum. Stratum 1 received radiotherapy with vorinostat, followed by up to 10 cycles of vorinostat and temsirolimus. Stratum 2 received up to 12 cycles of vorinostat and temsirolimus. Vorinostat was administered at a fixed dose of 230 mg/m2 daily on Days 1-8, and temsirolimus was administered on Days 1 and 8 at 25 mg/m2 (Dose level 1) or 35 mg/m2 (Dose level 2).

Six patients were enrolled, three in each stratum. No dose-limiting toxicity was observed, and most adverse effects were limited to Grades 1 or 2, including fatigue, myelosuppression, hyperlipidemia, hyperglycemia, elevated creatinine, nausea, vomiting, and headache. One patient experienced Grade 3 leukopenia. In the study, the MTD with acceptable toxicity was vorinostat 230 mg/m2 and temsirolimus 35 mg/m2.

Overall, the combination of temsirolimus and vorinostat is well-tolerated and safe, prompting the need for larger studies to investigate its efficacy.

The current standard treatment for hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer (BC) involves the use of anti-HER2 monoclonal antibodies combined with chemotherapy, followed by sequential endocrine therapy. However, crosstalk between the HR and HER2 pathways may cause drug resistance. Combining therapies targeting both the HR and HER2 pathways may be a rational approach for patients with HR+/HER2+ tumors, as this strategy could counteract resistance by blocking crosstalk in the receptor pathway. However, clinical data in this field remain limited. The present report describes the case of a patient with HR+/HER2+ late-stage BC who achieved a long-term partial response rate after receiving anti-HER2 combination chemotherapy followed by sequential treatment with endocrine therapy and cyclin-dependent kinase 4/6 (CDK4/6) inhibitors. The present case provides additional evidence suggesting that incorporating CDK4/6 inhibitors into standard targeted chemotherapy regimens may be an effective treatment option for patients with HR+/HER2+ BC.

Soft tissue sarcomas (STSs) are a group of rare cancers, among which nuclear protein in testis (NUT) sarcomas represent an ultra-rare subset driven by NUTM1 gene fusions. This article presents two unique cases of NUT sarcomas and conducts a comprehensive review of the literature to include an additional 61 cases. Our review reveals that NUT sarcoma exhibits a slightly higher incidence among women (male-to-female ratio of 1:1.03) and tends to manifest at a relatively young age (median age of 40 years). The most prevalent NUT partner genes were the MAD family in 52% of patients (33 of 63 patients, including MGA [n = 12], MXD4 [n = 12], MXD1 [n = 2], and MXI1 [n = 7]), CIC in 30% of patients (n = 19), and bromodomain (BRD) proteins in 8% of patients (n = 5 patients total, including BRD4 [n = 4] and BRD3 [n = 1]). Although 60% of NUT sarcomas (38 of 63 patients) are diagnosed in early stages, half of these patients (19 of 38 patients) experienced relapse despite curative-intent surgery. The median survival of the 21 patients evaluable for survival was 14 months. Finally, among 21 patients who received systemic therapy, only three patients receiving chemotherapy showed disease control, as defined by response or stability of the disease. This article emphasizes the importance of prompt diagnosis through immunohistochemistry and/or next-generation sequencing testing, advocates for the establishment of a NUT sarcoma registry, and emphasizes the need for clinical trials to advance drug development for this rare disease. Delving into a detailed analysis of pathogenesis of the distinct NUT fusions, this article reviews innovative treatment approaches to NUT sarcoma. These strategies include BRD and extraterminal (BET) inhibitors, trabectedin, inhibitors of the EP300 histone acetyltransferase, and histone deacetylase inhibitors such as vorinostat. In the absence of clinical trials, the results from this review suggest that trabectedin-based or ifosfamide-based regimens, particularly in combination with doxorubicin, may offer a reasonable approach as frontline therapy for NUT sarcomas.

Glucocorticoid receptor (GR) activity may mediate chemoresistance in advanced triple-negative breast cancer (TNBC). Preclinical studies demonstrate that GR antagonism can augment the effect of taxanes in TNBC models. We hypothesized that pretreatment with mifepristone, a potent GR antagonist, would enhance nab-paclitaxel efficacy in advanced TNBC.

This trial was terminated early due to poor accrual. 29 of 64 planned patients were enrolled. Patients were randomized to receive nab-paclitaxel with or without mifepristone; oral mifepristone 300 mg was administered the day prior and day of each dose of nab-paclitaxel. The primary endpoint was progression-free survival (PFS); secondary/exploratory endpoints included response rate and correlation of response with GR expression.

The addition of mifepristone to nab-paclitaxel did not improve PFS (3.0 m vs 3.0 m, p = 0.687) or overall response rate (23% vs 31.5%) compared to nab-paclitaxel alone. There was a trend towards improved overall survival in the combination group, primarily driven by one long-term responder. Increased rates of grade 3 neutropenia (46% vs 7%) and febrile neutropenia were observed in the combination arm, while other toxicities were similar in both groups. Increased GR expression was not correlated with clinical response in the combination arm.

While there were responders to the combination, the study was underpowered to meet the primary endpoint. Higher rates of neutropenia were observed in the combination, but overall it was well tolerated. Preclinical data in TNBC and clinical data in other malignancies support further investigation of GR modulators. Future studies should incorporate biomarkers to select patients who benefit from GR inhibition.

A growing body of evidence highlights the importance of microglia, the resident immune cells of the CNS, and their pro-inflammatory activation in the onset of many neurological diseases. Microglial proliferation, differentiation, and survival are highly dependent on the CSF-1 signaling pathway, which can be pharmacologically modulated by inhibiting its receptor, CSF-1R. Pharmacological inhibition of CSF-1R leads to an almost complete microglial depletion whereas treatment arrest allows for subsequent repopulation. Microglial depletion has shown promising results in many animal models of neurodegenerative diseases (Alzheimer's disease (AD), Parkinson's disease, or multiple sclerosis) where transitory microglial depletion reduced neuroinflammation and improved behavioral test results. In this review, we will focus on the comparison of three different pharmacological CSF-1R inhibitors (PLX3397, PLX5622, and GW2580) regarding microglial depletion. We will also highlight the promising results obtained by microglial depletion strategies in adult models of neurological disorders and argue they could also prove promising in neurodevelopmental diseases associated with microglial activation and neuroinflammation. Finally, we will discuss the lack of knowledge about the effects of these strategies on neurons, astrocytes, and oligodendrocytes in adults and during neurodevelopment.

To evaluate the results of inside stent therapy for unresectable malignant hilar biliary obstruction and identify factors related to stent patency duration.

Of 44 patients who underwent initial inside-stent placement above the sphincter of Oddi from April 2017 to December 2022, 42 with the resolution of jaundice (clinical success rate, 95.5%) were retrospectively analyzed. Univariate and multivariate logistic regression analysis identified factors associated with stent patency duration.

Univariate analysis revealed significant differences in the drainage method (406 days for unilateral drainage vs. 305 days for bilateral drainage of the right and left liver lobes, p = 0.022) with or without chemotherapy (406 days with vs. 154 days without, p = 0.038). Multivariate analysis (Cox proportional hazards analysis) revealed similar results, with unilateral drainage (p = 0.031) and chemotherapy (p = 0.048) identified as independent factors associated with prolonged stent patency. Early adverse events were observed in two patients (4.8%; one cholangitis, one pancreatitis).

Inside-stent therapy was safely performed in patients with malignant hilar biliary obstruction. Simple unilateral drainage and chemotherapy may prolong stent patency.

In patients receiving anti-cancer treatment, cachexia results in poorer oncological outcomes. However, there is limited understanding and no systematic review of oncological endpoints in cancer cachexia (CC) trials. This review examines oncological endpoints in CC clinical trials.

An electronic literature search of MEDLINE, Embase and Cochrane databases (1990-2023) was performed. Eligibility criteria comprised participants ≥ 18 years old; controlled design; ≥ 40 participants; and a cachexia intervention for > 14 days. Trials reporting at least one oncological endpoint were selected for analysis. Data extraction was performed using Covidence and followed PRISMA guidelines and the review was registered (PROSPERO CRD42022276710).

Fifty-seven trials were eligible, totalling 9743 patients (median: 107, IQR: 173). Twenty-six (46%) trials focussed on a single tumour site: eight in lung, six in pancreatic, six in head and neck and six in GI cancers. Forty-two (74%) studies included patients with Stage III/IV disease, and 41 (70%) included patients receiving palliative anti-cancer treatment. Ten studies (18%) involved patients on curative treatment. Twenty-eight (49%) studies used pharmacological interventions, 29 (50%) used oral nutrition, and two (4%) used enteral or parenteral nutrition. Reported oncological endpoints included overall survival (OS, n = 46 trials), progression-free survival (PFS, n = 7), duration of response (DR, n = 1), response rate (RR, n = 9), completion of treatment (TC, n = 11) and toxicity/adverse events (AE, n = 42). Median OS differed widely from 60 to 3468 days. Of the 46 studies, only three reported a significant positive effect on survival. Seven trials showed a difference in AE, four in TC, one in PFS and one in RR. Reported significances were unreliable due to missing adjustments for extensive multiple testing. Only three of the six trials using OS as the primary endpoint reported pre-trial sample size calculations, but only one recruited the planned number of patients.

In CC trials, oncological endpoints were mostly secondary and only few significant findings have been reported. Due to heterogeneity in oncological settings, nutritional and metabolic status and interventions, firm conclusions about CC treatment are not possible. OS and AE are relevant endpoints, but future trials targeting clinically meaningful hazard ratios will required more homogeneous patient cohorts, adequate pre-trial power analyses and adherence to statistical testing standards.

In the era of precision oncology, systemic therapies for colon cancer are becoming increasingly biomarker-led, with implications for patients in the neoadjuvant, adjuvant and metastatic settings. As the landscape for colon cancer treatment evolves and becomes more complex, it is important that all members of the multidisciplinary team keep abreast of developments to ensure the most effective care is delivered to patients. As core members of the colorectal multidisciplinary team, Radiologists play a central role throughout the patient journey. This review serves as an educational summary of current and emerging treatment pathways in colon cancer, standards for biomarker testing, mechanisms of action for key drugs, important treatment-related complications, relevant tumour biology that underpins patterns of disease and treatment response, and the specific implications systemic therapies have for cancer imaging and Radiologists. We also highlight the increasing role for radiology in patient stratification and the importance of imaging biomarkers. It is crucial that Radiologists understand the current landscape of colon cancer treatment and emerging strategies on the horizon in clinical trials. Only through engagement across the wider multidisciplinary team will we deliver true personalised medicine for patients with colon cancer.

Complex surgery during initial cancer treatment can limit surgical options when planning management of a secondary malignancy. Subtotal esophagectomy and pancreatoduodenectomy are the most invasive and difficult procedures in gastroenterological surgery. Surgical cases in which subtotal esophagectomy was performed after pancreatoduodenectomy with pancreaticogastrostomy are extremely rare and challenging procedures due to the resulting complicated anatomical changes.

A 60-year-old man with a history of conversion pancreatoduodenectomy with pancreaticogastrostomy for advanced pancreatic head cancer was diagnosed as having advanced thoracic esophageal squamous cell carcinoma. After neoadjuvant chemotherapy, we chose a two-staged surgery with thoracoscopic subtotal esophagectomy. Following percutaneous endoscopic gastrostomy, we performed subtotal esophagectomy, systematic lymph-node dissection, and esophagostomy as the first-stage operation. Fifty-six days later, we performed gastrointestinal reconstruction with pedicle jejunum and microvascular anastomosis by the percutaneous route as the second-stage operation. Postoperatively, the patient was relieved without major complications, and the tumors were amenable to curative pathologic resection.

The greatest advantages of staged surgery are to reduce surgical invasiveness and to circumvent the lower rate of curability. Our procedure reported here may be recommended as an option for staged resection and reconstruction in patients with advanced esophageal cancer after pancreatoduodenectomy with pancreaticogastrostomy.

Equivalence between HLX02 and trastuzumab sourced from the European Union (EU-trastuzumab), in combination with docetaxel, was demonstrated in a phase III study. This study aimed to evaluate the long-term efficacy and safety data after 3 years of follow-up.

Patients with previously untreated, HER2-positive metastatic breast cancer received intravenous HLX02 or EU-trastuzumab (initial dose of 8 mg/kg, followed by 6 mg/kg every 3 weeks for up to 12 months) in combination with docetaxel. Primary endpoint was the overall response rate up to week 24 (ORR24). Secondary endpoints including updated overall survival (OS), progression-free survival (PFS), safety and immunogenicity are reported in this long-term follow-up analysis.

After a median follow-up duration of 35.0 months, 270 out of the 649 enrolled patients had died; 128 (39.5 %) in the HLX02 and 142 (43.7 %) in the EU-trastuzumab group. Median OS was 37.3 (95 % CI 36.2, not evaluable [NE]) months and not reached (95 % CI 34.2, NE) (stratified HR 0.86 [95 % CI 0.68, 1.10]; p = 0.229), with a 3-year OS rate of 57.5 % and 54.0 %, respectively. Median PFS at this long-term follow-up assessment was 11.7 (95 % CI 11.5, 12.1) months for the HLX02 group and 10.6 (95 % CI 9.5, 11.7) months for the EU-trastuzumab group (stratified HR 0.86 [95 % CI 0.69, 1.06]; p = 0.158). No new safety concerns were reported until the end of the survival follow-up.

Long-term efficacy and safety were consistent with the previous findings. No clinically meaningful differences between HLX02 and reference trastuzumab were demonstrated.

Chinadrugtrials.org CTR20160526 (September 12, 2016), ClinicalTrials.gov NCT03084237 (March 20, 2017), EudraCT 2016-000206-10 (April 27, 2017).

This study aimed to compare the efficacy of pyrotinib, trastuzumab combined with chemotherapy with different lines therapy in human epidermal growth factor receptor 2- (HER2-) positive advanced breast cancer (ABC) and analyze the factors affecting the prognosis. A total of 84 patients with median age of 49 year-old. The mPFS of patients receiving first-line pyrotinib plus trastuzumab and chemotherapy was the longest (11 months) compared with second- and third line patients (p = 0.106). The objective response rate (ORR) and disease control rate (DCR) of the total population were 33.3% and 82.1% respectively. Subgroup analysis suggested that using pyrotinib plus trastuzumab and Albumin-bound paclitaxel was not inferior to combine with Vinorelbine in regards of PFS. Histological grade (OR: 0.233[0.069 ∼ 0.781], p = 0.018) and tumor location (OR: 0.286[0.087 ∼ 0.942], p = 0.040) were independent factors influencing the ORR. Multivariate cox analysis showed that Ki-67 was independently associated with increased risk of progression (HR: 1.843[1.044-3.254], p = 0.035). The most common adverse events were diarrhea (17.9%) and neutropenia (11.9%). In the first-, second- and third-line treatment, pyrotinib plus trastuzumab and chemotherapy is effective and safe. Pyrotinib and trastuzumab combined with Albumin-bound paclitaxel may be a potential ideal treatment plan for HER2-positive advanced breast cancer.

Intraoperative ultrasound-guided breast-conserving surgery guarantees real-time direct visualization of tumor and resection margins. We compared surgical, oncologic, and cosmetic outcomes between intraoperative ultrasound-guided breast-conserving surgery and traditional (palpation- or wire-guided) surgery across all breast cancer lesion types.

This prospective observational cohort study was conducted at the Veneto Institute of Oncology between January 2021 and October 2022. Patients with ductal carcinoma in situ, T1-2 invasive breast cancer, or post-neoadjuvant residual lesions, who were suitable for breast-conserving surgery were enrolled. A novel classification system categorized all breast cancer lesion types: solid palpable (type A); solid non-palpable (B); non-solid non-palpable (C); and post-neoadjuvant residual lesions (D). Main outcomes included involved margin rates, excision volumes, and cosmetic satisfaction.

In total, 206 patients were enrolled, with 103 receiving traditional (palpation- or wire-guided) surgery and 103 undergoing intraoperative ultrasound-guided breast-conserving surgery. Despite similar tumor volumes, intraoperative ultrasound-guided breast-conserving surgery resulted in significantly smaller excised volumes (P = .024), greater tumor volume to specimen volume ratios (P = .002), and lower involved margin and reoperation rates (P = .002 and P = .01, respectively), in addition to a wider closest margin width (P < .001). Stratified analyses demonstrated superior performance of intraoperative ultrasound-guided breast-conserving surgery across all breast cancer lesion types, with notable improvements observed in the most challenging ones (types C and D). One-year follow-up assessments revealed significantly greater patient satisfaction levels after intraoperative ultrasound-guided breast-conserving surgery (P < .001), with specimen volume identified as the sole significant predictor of cosmetic satisfaction (P = .001).

Intraoperative ultrasound-guided breast-conserving surgery showed clear superiority over traditional (palpation- or wire-guided) surgery in oncologic, surgical, and cosmetic outcomes, as demonstrated by a comprehensive stratified analysis encompassing all breast cancer lesion types. Intraoperative ultrasound-guided breast-conserving surgery represents the latest and most effective paradigm for precision breast-conserving surgery.

The expression of programmed cell death-ligand 1 (PD-L1) and mutation in epidermal growth factor receptor (EGFR) are biomarkers used for perioperative treatment of lung adenocarcinoma. However, the clinical significance of PD-L1 expression in surgically resected EGFR-mutant lung adenocarcinoma remains unclear. We conducted a real-world database of patients with surgically resected lung adenocarcinoma from 2015 to 2018 was constructed across 21 centers in Japan. The association among PD-L1 expression, EGFR mutations, and prognosis was evaluated. Among 847 patients, PD-L1 expression was negative (tumor proportion score [TPS] < 1%) in 429 (51%), weakly positive (TPS = 1%-49%) in 275 (32%), and strongly positive (TPS ≥50%) in 143 (17%) patients. EGFR mutations were detected in 331 (39%) patients. PD-L1 expression was associated with poor recurrence-free survival (RFS) (p < .001) in both EGFR-mutant and wild-type patients. However, in EGFR-mutant patients, PD-L1 expression was not associated with overall survival (OS) (p = .506). Multivariable analysis confirmed an association between PD-L1 expression and RFS but not OS. Furthermore, in EGFR-mutant patients treated with EGFR-tyrosine kinase inhibitor (EGFR-TKI) treatment post-relapse, PD-L1 expression was not associated with overall response rate (p = .714), disease control rate (p = .554), or progression-free survival (p = .660). In conclusion, PD-L1 expression predicted poor RFS-independent EGFR status but did not show any association with OS in EGFR-mutant patients. The efficacy of post-relapse EGFR-TKI treatment was independent of PD-L1 expression. The significance of PD-L1 expression in perioperative EGFR-TKI therapy should be evaluated.

To compare the effectiveness of transarterial embolization (TAE) using a liquid embolic (LE) with that of TAE using a particle embolic (PE) based on radiographic and histologic responses in a translational rat model of hepatocellular carcinoma (HCC).

HCC was induced in Wistar rats using diethylnitrosamine. Tumor response was determined through Response Evaluation Criteria in Solid Tumors applied to T2-weighted magnetic resonance (MR) imaging scans. Tumor necrosis and hypoxia were assessed through hematoxylin and eosin and pimonidazole staining, respectively. Statistical analyses were performed using chi-square tests, Kaplan-Meier estimates, logistic regression, and 1-way analysis of variance, with significance set at P < .05.

Twenty-nine rats were randomized to TAE with LE (n = 13), PE (n = 13), or sham (n = 3). LE TAE demonstrated a significantly higher objective response rate (83%) compared with PE TAE (28%; χ2 = 11.25; P = .0008). Complete responses were observed in 50% of the LE-treated tumors versus 10% in the PE-treated group. LE TAE prolonged local progression-free survival (hazard ratio, 0.31; P = .032). Histologic analysis of an additional 16 rats randomized to TAE with LE (n = 7), PE (n = 6), or sham (n = 3) showed greater necrosis in LE-treated tumors compared to PE-treated tumors. LE induced a significantly greater reduction in viable tumor tissue (P = .009) and proportionally larger necrotic and necrotic + hypoxic tissue areas compared with PE (P = .003).

LE significantly enhanced the therapeutic effectiveness of TAE in a rat model of HCC compared with PE. These results highlight the potential of LEs to improve ischemia and necrosis, thereby offering a promising option for improving the effectiveness of embolization for HCC treatment.

Advances in immune oncology have established immunotherapy as the first-line standard treatment for lung cancer; however, its efficacy remains limited to a subset of patients. Developing predictive biomarkers within the tumor microenvironment (TME) to assess the efficacy and prognosis of immunotherapy can enhance drug development and treatment strategies. Immuno-positron emission tomography (ImmunoPET) non-invasively visualizes the biological distribution of key targets in the TME using highly specific, radiolabeled tracers. PET imaging of the TME can serve as a reliable biomarker for predicting and monitoring responses to immune therapy, complementing existing immunohistochemical techniques. This review will focus on the development of ImmunoPET biomarkers, as well as the application of corresponding tracers and radionuclides in lung cancer. We will focus on available clinical tracers and those under development, outlining each TME target and its clinical validation for tumor immunotherapy efficacy and prognosis, while discussing the latest advances that may enhance ImmunoPET in future.

Datopotamab deruxtecan (Dato-DXd) is a trophoblast cell-surface antigen-2-directed antibody-drug conjugate with a highly potent topoisomerase I inhibitor payload. The TROPION-Lung05 phase II trial (ClinicalTrials.gov identifier: NCT04484142) evaluated the safety and clinical activity of Dato-DXd in patients with advanced/metastatic non-small cell lung cancer (NSCLC) with actionable genomic alterations progressing on or after targeted therapy and platinum-based chemotherapy.

Patients received Dato-DXd 6 mg/kg once every 3 weeks. The primary end point was objective response rate (ORR) by blinded independent central review. Secondary end points included duration of response (DOR), safety, tolerability, and survival.

Among 137 patients who received at least 1 dose of Dato-DXd, 71.5% received at least three lines of prior therapies for advanced/metastatic disease. Overall, 56.9% had EGFR mutations and 24.8% had ALK rearrangements. Median treatment duration was 4.4 months (range, 0.7-20.6). The confirmed ORR was 35.8% (95% CI, 27.8 to 44.4) overall, and 43.6% (95% CI, 32.4 to 55.3) and 23.5% (95% CI, 10.7 to 41.2) in those with EGFR mutations and ALK rearrangements, respectively. The median DOR was 7.0 months (95% CI, 4.2 to 9.8), and the overall disease control rate was 78.8% (95% CI, 71.0 to 85.3). Grade ≥3 treatment-related adverse events (TRAEs) occurred in 28.5% of patients. The most common TRAE was stomatitis (preferred term; any grade: 56.2%; grade ≥3: 9.5%). Five (3.6%) patients experienced adjudicated treatment-related interstitial lung disease/pneumonitis, with 1 (0.7%) grade 5 event.

Encouraging and durable antitumor activity was observed with Dato-DXd in this heavily pretreated advanced/metastatic NSCLC population with actionable genomic alterations. The rate of treatment-related grade ≥3 toxicities was comparable with previous observations, and no new safety signals were observed.

The SOFT (Stereotactic ablative radiotherapy of infra-diaphragmatic sOFT tissue metastases) trial assesses the safety and efficacy of risk-adapted MR-guided stereotactic ablative radiotherapy (SABR) of infra-diaphragmatic soft tissue metastasis in patients with oligometastatic disease (OMD) (clinicaltrials.gov ID NCT04407897). This paper reports the one-year efficacy analysis and evaluates associations between local control (LC) and clinical and dosimetric parameters.

This investigator-initiated, multicenter, single-arm, phase 2 study recruited patients from four MR-linac centers in Denmark and the US. Patients with De novo or recurrent OMD with ≤5 metastases in ≤3 organs and patients with induced OMD or oligoprogressive disease (OPD) with ≤3 metastases were eligible. Fractionation schemes were 45-75 Gy in 3-8 fractions.

The trial included 121 patients with 147 oligometastatic lesions, primarily in the liver (41 %), lymph nodes (35 %), or adrenal glands (14 %). The median follow-up time was 13.0 months, interquartile range (IQR) (11.7,13.7) months. The 1-year LC rate was 89 %, 95 % confidence interval (CI) (83,94 %). We did not observe any statistically significant associations between LC and clinical and dosimetric parameters. The median progression-free survival was 7.1 months, 95 % CI (6.0,9.4). One- and two-year overall survival was 82.6 %, 95 % CI (76.2 %,89.7 %), and 65.1 %, 95 % CI (56.4 %,75.3 %). Sixty-one patients (50 %) were kept off systemic therapy throughout the one-year follow-up.

In our study, treatment with risk-adapted, MR-guided SABR resulted in a high one-year local control and survival rate and could keep half of the patients off systemic therapy within the first year of follow-up.

This is a single arm, open label trial to assess the safety and efficacy of NALIRIFOX in Japanese participants who have not previously received therapy for metastatic adenocarcinoma of the pancreas. Forty-one participants will receive the treatment NALIRIFOX (liposomal irinotecan, 5-fluorouracil, levoleucovorin and oxaliplatin) until progression or unacceptable toxicity. Anti-tumor activity will be evaluated in terms of objective response rate according to RECIST v1.1 by independent central review. Safety will be carefully monitored, with a dedicated Safety Monitoring Committee reviewing the data from the initial six participants to safeguard the well-being of all individuals involved in the study. Other evaluations will include pharmacokinetics and the relationship between mutations in the UGT1A1 genes and safety. This study aims to show that the results of the NAPOLI 3 study in the global population can be reproduced in the Japanese population.Clinical trials registration: NCT06225999 (clinicaltrials.gov); jRCT2031230733 (Japanese clinical trials registry).

In 1948, the indirect ophthalmoscope revealed full intra-ocular retinoblastoma, documented on paper with coloured pencils. At SickKids, eCancerCareRB (eCCRB) digital drawings and timeline have facilitated patient care, education, and research.

Each child's eCCRB timeline shows treatments and dates. The SwimmerRB tool presents eCCRB data for research with time "0" start of intervention. Any tumour treatment after the intervention indicates recurrence; no cancer treatments indicate complete response. To further quantify the impact of retinoblastoma on child/family, we arbitrarily assigned a "consequence" score to each standard treatment (i.e., focal = 1, intra-arterial chemotherapy = 3, enucleation last eye = 30). Retrospective control eCCRB patients were matched to study participants by similar "propensity" scores before time "0." Postintervention scores indicated effectiveness.

eCCRB included 700 patients with retinoblastoma treated between 2001 and 2023 at SickKids. SwimmerRB facilitated comparing eCCRB patients treated with single- versus triple-drug intra-arterial chemotherapy. In the phase 1 Chemoplaque Clinical Trial, SwimmerRB analysis compared number of treatments before and after the Chemoplaque. Consequence scores quantitating negative outcomes will be refined by quality-of-life studies including those with lived experience. DEPICT HEALTH (DEPICT) on the cloud-hosted technology will soon replace eCCRB (now-outdated technology), offering digital retinoblastoma care to the world.

eCCRB (only in SickKids) is the time-tested prototype for DEPICT on the cloud. DEPICT brings digital retinal drawings, timeline, research, and clinical consultation to full view for families as partners in retinoblastoma care. DEPICT will be offered through the International Retinoblastoma Consortium to any site caring for children with retinoblastoma.

Recent discussions about the utilization of real-world data (RWD) and real-world evidence (RWE) have been more focused on drug development for regulatory approval rather than during the post-marketing stage. In Japan, RWD/RWE have been practically utilized as an external control for drug approval. Most cases were related to orphan diseases where the feasibility of conducting randomized controlled clinical trials was generally low. The utilization of RWD/RWE as an external control provides additional information that can support regulatory review for drug approval. However, many points should be taken into consideration through all stages of a study that is based on RWD/RWE, including planning, analysis, and interpretation. In this article, we present our recent review experience focusing on efficacy evaluations with an external control based on RWD/RWE that were submitted as a part of new drug applications in Japan, and we describe our regulatory consideration of the utilization of RWD/RWE for drug evaluation and approval. Points described in this article promote appropriate drug development based on RWD/RWE and facilitate a proper discussion about RWD/RWE utilization with PMDA. Further accumulation of regulatory experience in PMDA with RWD/RWE utilization will enhance our knowledge and contribute to better regulatory decision making for drug approvals based on RWD/RWE.

Patients with advanced penile squamous cell carcinoma (PSCC) have poor outcomes and very limited therapeutic options are available. Most PSCC cases have high PD-L1 expression, which is associated with worse prognosis. Immunotherapy targeting PD-L1 could benefit patients with PSCC. Our aim was to evaluate the efficacy and safety of the anti-PD-1 antibody retifanlimab in patients with advanced/metastatic PSCC.

ORPHEUS was a single-arm, multicenter, phase 2 trial in 18 patients with advanced/metastatic PSCC, previously untreated with anti-PD-1/anti-PD-L1 agents. Patients received retifanlimab 500 mg intravenously every 4 wk for up to 2 yr. The primary endpoint was the objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors v1.1. Secondary endpoints included the clinical benefit rate (CBR), disease control rate, duration of response (DoR), time to response, progression-free survival (PFS), overall survival (OS), maximum tumor shrinkage, and safety. The Wilson method was used for the primary endpoint, and the Clopper-Pearson and Kaplan-Meier methods for secondary endpoints.

Median follow-up was 7.2 mo. The ORR was 16.7% (95% confidence interval [CI] 5.8-39.2); three patients had a partial response. Median DoR was 3.3 mo (range 1.8-8.5). The CBR was 22.2% (95% CI 6.4-47.6%). Median PFS was 2.0 mo (95% CI 1.6-3.3) and median OS was 7.2 mo (95% CI 3.0-9.8). One patient (5.6%) experienced grade 3 treatment-related adverse events (AEs). There were no grade >= 4 treatment-related AEs. The small sample size is the main limitation.

Single-agent retifanlimab exhibited signals of clinical activity in advanced/metastatic PSCC, with no new safety signals. Further investigation of retifanlimab in this setting is warranted.

Advanced penile cancer of the squamous cell type is a rare tumor with poor prognosis. The aggressiveness of this cancer is usually associated with high levels of a protein called PD-L1. We investigated whether retifanlimab, an immunotherapy drug against PD-1, has activity against this type of penile cancer. Tumor regression or stabilization occurred in one-third of the patients and the side effects were manageable.

The TRK inhibitor larotrectinib is US Food and Drug Administration approved for NTRK fusion-positive solid tumors that lack a satisfactory alternative or have progressed after treatment but has not been systematically studied as a frontline therapy with a defined duration of treatment. ADVL1823 evaluated larotrectinib in patients with newly diagnosed NTRK fusion-positive solid tumors with response-adapted duration of therapy and local control.

Patients received larotrectinib twice daily in 28-day cycles for a predefined duration of treatment, ranging from 6 to 26 cycles depending on response to therapy and surgical resectability. The primary end point was the objective response rate (ORR) within six cycles in patients with infantile fibrosarcoma (IFS); patients with other histologic diagnoses were analyzed in a separate cohort. Secondary objectives included event-free survival (EFS) and overall survival (OS).

Thirty-three patients were enrolled: 18 with IFS and 15 with other solid tumors. The ORR within six cycles was 94% (17/18; 95% adjusted CI, 72.7 to 98.6) among children with IFS and 60% (9/15; 95% CI, 32.3 to 83.7) among children with other solid tumors. Six percent (2/33; 95% CI, 0.7 to 22.2) patients developed progressive disease while on therapy. Two-year EFS and OS among these groups were 82.2% (95% CI, 54.3 to 93.9) and 93.8% (95% CI, 63.2 to 99.1) for IFS and 80% (95% CI, 50.0 to 93.1) and 93.3% (95% CI, 61.3 to 99.0) for other solid tumors, respectively. Patients undergoing surgical resection of their tumor had prolonged EFS, with only 1 of 16 such patients experiencing disease progression. Four of 33 patients had dose-limiting toxicities.

Larotrectinib is highly active in patients with newly diagnosed NTRK fusion-positive solid tumors. Larotrectinib should be a frontline option for patients with IFS and other NTRK fusion-positive solid tumors. Local control with surgical resection remains important in the treatment of patients with IFS.

Benefits of neoadjuvant treatment for pancreatic cancer with major vessel invasion has been demonstrated through randomized controlled trials; however, the optimal neoadjuvant treatment strategy remains controversial, especially for radiotherapy. Therefore, we aimed to evaluate the efficacy and safety of neoadjuvant radiotherapy followed by chemotherapy and the optimal time interval to undergo surgery after radiotherapy in (borderline) resectable pancreatic cancer.

Between 2013 and 2022, patients with (borderline) resectable pancreatic cancer with vessel contact who received 5-fluorouracil with leucovorin, oxaliplatin, and irinotecan or gemcitabine and nanoparticle albumin-bound paclitaxel as initial treatment following surgery were included. Patients who received radiotherapy after chemotherapy and those who did not were matched using 1:1 nearest-neighbor propensity scores. Propensity scores were measured using the tumor size at initial image, duration of neoadjuvant chemotherapy, and responsiveness to neoadjuvant chemotherapy.

Of 212 patients, 166 patients were retrieved for the matched cohort. Patients who received radiotherapy had significantly better postoperative survival, local control, and R0 resection rates than those who did not. Furthermore, patients who underwent surgery within 4 weeks after completing radiotherapy had lower intraoperative blood loss and a clinically relevant postoperative pancreatic fistula rate than those who underwent surgery after more than 4 weeks.

In patients with (borderline) resectable pancreatic cancer with vessel contact who were scheduled for curative-intent surgery after neoadjuvant chemotherapy, additional radiotherapy was associated with better postoperative survival and local control. Furthermore, our findings suggested that scheduling surgery within 4 weeks following radiation therapy might enhance the perioperative outcomes.

The purpose of this study was to evaluate the impact of probability map threshold on pleural mesothelioma (PM) tumor delineations generated using a convolutional neural network (CNN). One hundred eighty-six CT scans from 48 PM patients were segmented by a VGG16/U-Net CNN. A radiologist modified the contours generated at a 0.5 probability threshold. Percent difference of tumor volume and overlap using the Dice Similarity Coefficient (DSC) were compared between the reference standard provided by the radiologist and CNN outputs for thresholds ranging from 0.001 to 0.9. CNN-derived contours consistently yielded smaller tumor volumes than radiologist contours. Reducing the probability threshold from 0.5 to 0.01 decreased the absolute percent volume difference, on average, from 42.93% to 26.60%. Median and mean DSC ranged from 0.57 to 0.59, with a peak at a threshold of 0.2; no distinct threshold was found for percent volume difference. The CNN exhibited deficiencies with specific disease presentations, such as severe pleural effusion or disease in the pleural fissure. No single output threshold in the CNN probability maps was optimal for both tumor volume and DSC. This study emphasized the importance of considering both figures of merit when evaluating deep learning-based tumor segmentations across probability thresholds. This work underscores the need to simultaneously assess tumor volume and spatial overlap when evaluating CNN performance. While automated segmentations may yield comparable tumor volumes to that of the reference standard, the spatial region delineated by the CNN at a specific threshold is equally important.

The objective of this study is to assess the differential expression of ferroptosis suppressor protein 1 (FSP1) in relation to clinical features, platinum resistance, and recurrence in epithelial ovarian cancer (EOC). In addition, the potential significance of FSP1 in EOC as a predictor of platinum resistance and recurrence in EOC was explored. Patients with pathologically confirmed EOC who underwent surgical treatment were included in this analysis. Immunohistochemistry was employed to evaluate FSP1 expression in ovarian tissues, with quantitative analysis performed on the samples. Clinical data were collected during follow-up, and patients were categorized according to platinum resistance and recurrence criteria. Statistical analysis was conducted using SPSS version 27.0. A total of 40 tissue samples from patients with EOC were analyzed, along with 21 samples from benign ovarian tumors and 20 samples from normal ovarian tissues. The expression of FSP1 was significantly higher in the EOC group compared to both benign and normal tissue groups. Meanwhile, the expressions of FSP1 were higher in groups with clinically advanced stages, high-grade carcinoma, presence of cancerous ascites, lymph node metastasis, and in the clear cell EOC group, compared to those with clinically early stages, low-grade carcinoma, absence of cancerous ascites, no lymph node metastasis, and other pathological subtypes. A positive linear correlation was identified between FSP1 expression in EOC tissues and serum levels of CA125 and human epididymis protein 4 at the time of diagnosis. The elevated expression of FSP1 is positively correlated with serum CA125 and human epididymis protein 4 levels at the time of diagnosis, which is a risk factor for EOC drug resistance and recurrence. These findings suggest that FSP1 may serve as a valuable biomarker for predicting platinum resistance and recurrence in patients with EOC.

The aim of this study was to investigate the clinical significance of microRNA-4449 (miR-4449) in patients attacked by non-small cell lung cancer (NSCLC) undergoing thoracic paravertebral block (TPVB) thoracotomy.

A total of 122 patients diagnosed with NSCLC and 101 healthy individuals were recruited in this case-control study. Quantitative real-time polymerase reaction time (qRT-PCR) assay was applied to quantify the serum levels of miR-4449 in all participants. To assess the diagnostic potential of miR-4449, receiver operating characteristic (ROC) curves were constructed. Additionally, the prognostic value of miR-4449 was evaluated using Kaplan-Meier method and Cox regression analyses. The possible target genes and related proteins of miR-4449 were predicted via bioinformatics analysis.

MiR-4449 expression was notably reduced in NSCLC patients relative to healthy volunteers (P < 0.001), with the area under the curve (AUC) reaching 0.952, demonstrating its ability to effectively differentiate between NSCLC patients and healthy individuals. Serum levels of miR-4449 were negatively in relation to tumor node metastasis stage and lymph node metastasis (P < 0.05). Moreover, a significant increase in miR-4449 expression was observed in patients following TPVB thoracotomy, as compared to pre-operative levels (P < 0.001). The AUC of 0.884 further highlighted its potential to distinguish between the effective group and the invalid group. Notably, patients expressing high levels of miR-4449 exhibited improved overall survival (P < 0.001), and miR-4449 (P < 0.001, HR = 2.290, 95 % = 1.450-3.615) was identified as an independently prognostic predictor for NSCLC. Bioinformatics analysis of miR-4999 target genes revealed key tumor-associated pathways and proteins, offering valuable insights into its molecular mechanisms in NSCLC.

Serum levels of miR-4449 were significantly decreased in patients with NSCLC and exhibited a correlation with the severity of the tumor. Furthermore, miR-4449 emerged as a potential prognostic biomarker, offering valuable insight into the clinical outcome for NSCLC undergoing TPVB thoracotomy.

Immune checkpoint inhibitors (ICIs) are playing a significant role in the treatment of hepatocellular carcinoma (HCC). This study aims to explore the prognostic value of alpha-fetoprotein (AFP) and initial tumor shape irregularity in patients treated with ICIs.

In this retrospective, multi-center study, 296 HCC patients were randomly divided into the training set and the validation set in a 3:2 ratio. The training set was used to evaluate prognostic factors and to develop an easily applicable ATSI (AFP and Tumor Shape Irregularity) score, which was verified in the validation set.

The ATSI score was developed from two independent prognostic risk factors: baseline AFP ≥ 400 ng/ml (HR 1.73, 95% CI 1.01-2.96, P = 0.046) and initial tumor shape irregularity (HR 1.94, 95% CI 1.03-3.65, P = 0.041). The median overall survival (OS) was not reached (95% CI 28.20-NA) in patients who met no criteria (0 points), 25.8 months (95% CI 14.17-NA) in patients who met one criterion (1 point), and 17.03 months (95% CI 11.73-23.83) in patients who met two criteria (2 points) (P = 0.001). The median progression-free survival (PFS) was 10.83 months (95% CI 9.27-14.33) for 0 points, 8.03 months (95% CI 6.77-10.57) for 1 point, and 5.03 months (95% CI 3.83-9.67) for 2 points (P < 0.001). The validation set effectively verified these results (median OS, 37.43/24.27/14.03 months for 0/1/2 points, P = 0.028; median PFS, 13.93/8.30/4.90 months for 0/1/2 points, P < 0.001).

The ATSI score can effectively predict prognosis in HCC patients receiving ICIs.