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Purpose: To examine the long-term performance of bonded all-ceramic restorations, specifically veneers, in patients with amelogenesis imperfecta (AI). There are few studies of long-term outcomes using a minimally invasive procedure in these patients. This aspect is essential when treating young patients. All-ceramic restorations, especially veneers, offer a more tissue-preserving treatment but rely on successful bonding. However, due to the defect enamel in AI patients, the bond strength is lower. Materials and Methods: A retrospective evaluation of 40 subjects with AI (26 women, 14 men) was provided with a total of 360 bonded restorations (282 veneers, 78 crowns). The restorations were evaluated according to complications, survival, and success rate. Results: The patients were observed up to 25.3 years (mean 15.4 ± 4.3 years). The mean age when receiving the restorations was 18.5 ± 4.2 years. In total, 59 (16.4%) restorations with prosthetic complications were made, 29 of which (8.1%) were remade (6 due to esthetic reasons, all in one patient) and 30 (8.3%) were recemented (60% caused by trauma). We found 11 teeth with caries and 3 with endodontic complications. The overall survival rate was 91.9%, and the overall success rate was 83.6%. Conclusions: Bonded all-ceramic restorations with no active retention in AI patients have excellent performance. The most common complications were debonding and fractures. The treatment should be based on individual indications and be preceded by a multidisciplinary approach. [ABSTRACT FROM AUTHOR]

BACKGROUND: [177Lu]Lu-PSMA-617 (177Lu-PSMA-617) prolonged life in patients with metastatic castration-resistant prostate cancer (mCRPC) in VISION (NCT03511664). However, distinguishing between patients likely and unlikely to respond remains a clinical challenge. We present the first multivariable models of outcomes with 177Lu-PSMA-617 built using data from VISION, a large prospective phase 3 clinical trial powered for overall survival. METHODS: Adults with progressive post androgen receptor pathway inhibitor and taxane prostate-specific membrane antigen (PSMA)-positive mCRPC received 177Lu-PSMA-617 plus protocol-permitted standard of care (SoC) or SoC alone. In this post hoc analysis, multivariable Cox proportional hazards models of overall survival (OS) and radiographic progression-free survival (rPFS), and a logistic regression model of prostate-specific antigen response (≥50% decline; PSA50) were constructed and evaluated using C-index or receiver operating characteristic (ROC) analyses with bootstrapping validation. Nomograms were constructed for visualisation. FINDINGS: Patients were randomised between June 2018 and October 2019. Data from all 551 patients in the 177Lu-PSMA-617 arm were analysed in multivariable modelling. The OS nomogram (C-index, 0.73; 95% confidence interval [CI], 0.70-0.76) included whole-body maximum standardised uptake value (SUVmax), time since diagnosis, opioid analgesic use, aspartate aminotransferase, haemoglobin, lymphocyte count, presence of PSMA-positive lesions in lymph nodes, lactate dehydrogenase (LDH), alkaline phosphatase (ALP), and neutrophil count. The rPFS nomogram (C-index, 0.68; 0.65-0.72) included SUVmax, time since diagnosis, opioid analgesic use, lymphocyte count, presence of liver metastases by computed tomography, LDH, and ALP. The PSA50 nomogram (area under ROC curve, 0.72; 95% CI, 0.68-0.77) included SUVmax, lymphocyte count and ALP. Performances of the OS and rPFS models were maintained when they were reconstructed excluding SUVmax. INTERPRETATION: These models of outcomes with 177Lu-PSMA-617 are the first built using prospective phase 3 data. They show that a combination of pretreatment laboratory, clinical, and imaging parameters, reflecting both patient and tumour status, influences outcomes. These models are important for aiding treatment selection, patient management, and clinical trial design. FUNDING: Novartis.

BACKGROUND/OBJECTIVES: The aim of this study was to estimate the effect of a 6 months treatment course of the innate immune modulator NP001 (a pH-adjusted intravenous formulation of purified sodium chlorite), on disease progression, as measured by overall survival (OS) in patients with amyotrophic lateral sclerosis. METHODS: Blinded survival data were retrospectively collected for 268 of the 273 patients who had participated in two phase 2 placebo-controlled clinical trials of NP001 (ClinicalTrials.gov: NCT01281631 and NCT02794857) and received at least one dose of either 1 mg/kg or 2 mg/kg of NP001 as chlorite based on actual body weight, or placebo. Kaplan-Meier methods were used on the intent-to-treat population to estimate survival probabilities. RESULTS: In the overall population, the median OS was 4.8 months (2.7 years [95% CI: 2.3, 3.5] in the 2 mg/kg NP001group and 2.3 years [95% CI: 1.8, 2.9] in the placebo group). Hazard ratio (HR): 0.77 (95% CI: 0.57, 1.03), p = 0.073. Among patients aged ≤ 65 years, the median OS for the 2 mg/kg NP001 group was 10.8 months (3.3 years [95% CI: 2.4, 3.8] in the 2 mg/kg NP001 group and 2.4 years [95% CI: 1.7, 3.3] in the placebo group). HR: 0.69 (95% CI: 0.50, 0.95). No differences were observed in the 1 mg/kg NP001 group or in patients aged > 65 years. CONCLUSIONS: The findings from this study suggest that a 6 months treatment course of NP001 resulted in a 4.8-month increase in overall survival in patients with ALS. The findings from this study indicate that targeting inflammation associated with the innate immune system may provide a pathway for new therapeutic options for the treatment of ALS.

BackgroundImmune checkpoint inhibitor (ICI) therapies have become increasingly popular treatment options for patients with cancer, even for patients in non-metastatic settings. Survival and responses have been reported for individual tumor types, but little is known about these outcomes, collectively. We sought to provide an overview of overall survival (OS) and progression-free survival (PFS) in ICI drugs tested in registration trials.MethodsIn a cross-sectional analysis of US FDA oncology ICI drug approvals (2011-2023), we searched for supporting ICI registration trials. We characterized these trials, regarding differences in median OS and PFS between patients in intervention and control arm participants in ICI registration trials; percentage of patients who receive ICI crossover; and whether there is correlation between the percentage of crossover and differences in OS or PFS.ResultsFifty-six (54.4 %) approvals had trials that reported median OS for both intervention and control arms (median difference was 2.8 months; IQR: 2.2 to 5.0 months). Sixty-five (63.1 %) approvals had trials that reported PFS data for both arms (median of 0.9 months; IQR: -0.2 to 3.0 months). Subsequent therapy was common (median=18.9 %) and was significantly correlated with a higher difference in median OS in all studies with reported differences (R2 =0.15; p = 0.001).ConclusionICIs are increasingly used in the treatment of cancer, yet the median OS improvement is modest, and many ICIs have not been tested for OS benefit. OS is the outcome most meaningful for patients, and drug regulation should require better testing and reporting of these data.

BACKGROUND: The US Food and Drug Administration (FDA) has expanded the use of surrogate markers in drugs approved for oncology/hematology indications. This has likely resulted in a greater number of approvals and possibly drugs coming to market faster, but it is unknown whether these drugs also improve overall survival (OS) for patients taking them. METHODS: We sought to estimate the percentage of oncology drugs that have shown to improve OS in a cross-sectional analysis of US FDA oncology drug approvals (2006-2023). We searched for OS data in registration trials and the peer-reviewed literature. RESULTS: We found 392 oncology drug approvals. Eighty-seven (22%) drug approvals were based on OS, 147 drug approvals were later tested for OS benefit (38% of all approvals and 48% of drugs approved on a surrogate), and 130 (33%) have yet to be tested for OS benefit. Of the 147 drug approvals later tested for OS, 109 (28% of all approvals and 74% of drugs later tested for OS) have yet to show OS benefit, whereas 38 (10% of all approvals and 26% of drugs later tested for OS benefit) were later shown to have OS benefit. In total, 125 out of 392 (32%) drugs approved for any indication have been shown to improve OS benefit at some point, and 267 (68%) have yet to show approval. CONCLUSION: About 32% of all oncology drug approvals have evidence for an improvement in OS. Higher standards are needed in drug regulation to ensure that approved drugs are delivering better patient outcomes, specifically in regards to survival.

BackgroundBone biomarkers are strongly prognostic for overall survival (OS) in men with castration-resistant prostate cancer but not fully established for hormone-sensitive prostate cancer (HSPC).ObjectiveBone biomarkers in HSPC were prospectively evaluated as part of a phase 3 study of androgen deprivation therapy ± the CYP17 inhibitor orteronel.Design, setting, and participantsPatients were randomly divided into training (n = 316) and validation (n = 633) sets. Recursive partitioning and Cox proportional hazard models were employed.Outcome measurements and statistical analysisBone resorption (C-telopeptide and pyridinoline) and bone formation markers (C-terminal collagen propeptide and bone alkaline phosphatase) were assessed from patient sera.Results and limitationsOf 1279 men, 949 had evaluable baseline bone biomarkers. Optimal cutoffs were identified to define elevated levels of each of the four biomarkers (all p

Aim: To outline the demographic and clinical features, treatment approaches and clinical outcomes of patients treated with palbociclib as the initial therapy for HR+/HER2- advanced or metastatic breast cancer (aBC/mBC) in private healthcare facilities in Brazil. Materials & methods: This study involved a retrospective review conducted from June 2022 to May 2023. Results: The study included 121 patients, with an average age of 54.4 years, and 82 (67.7%) were menopausal at the time of diagnosis. Of these, 51 patients (42.1%) were treated with palbociclib and fulvestrant, while 67 patients (55.8%) received palbociclib and aromatase inhibitors. Most patients (65.3%) did not need to adjust their doses. The progression-free survival rates were 78% at 6 months and 60% at 12 months. Overall survival rates were 86% at 6 months and 70% at 12 months. Conclusion: Palbociclib combinations show promising effectiveness in managing HR+/HER2- advanced or metastatic breast cancer. Plain Language Summary Treatment & results in Brazilian women with advanced or metastatic breast cancer given palbociclib Breast cancer is a major health issue worldwide, and it is the most common cancer among women in Brazil, with death rates on the rise. A significant portion of breast cancer cases are hormone receptor-positive (HR+) and HER2-negative (HER2-), making targeted treatments essential. One such treatment is palbociclib, a medication that inhibits Cyclin-dependent kinase 4 and 6 (CDK4/6), enzymes important in cell division. Clinical trials such as PALOMA-1, PALOMA-2 and PALOMA-3 have shown that palbociclib can help patients with advanced or metastatic HR+/HER2- breast cancer live longer without their disease getting worse. Studies in real-world settings around the world have confirmed these benefits, evaluating how well the treatment works over time. Palbociclib was approved for use in Brazil in 2018. This study looks back at the records of women treated with palbociclib in private healthcare settings in the country. It aims to provide crucial information which can help guide future treatment decisions. Article highlights Breast cancer is a leading cause of cancer-related deaths among females worldwide, with Brazil reporting around 66,000 new cases and over 16,000 deaths in 2017, making it the most prevalent neoplasm affecting women across all regions of the country. Palbociclib, a first-in-class CDK4/6 inhibitor, has shown significant efficacy in clinical trials for HR+/HER2- advanced/metastatic breast cancer, demonstrating improved progression-free survival rates in the PALOMA-1, PALOMA-2 and PALOMA-3 trials. This study aims to describe the demographics, clinical attributes, treatment patterns and outcomes of Brazilian women receiving palbociclib as a first-line treatment for HR+/HER2- advanced/metastatic breast cancer in private healthcare institutions, following its approval in Brazil in February 2018. Data was collected from 13 study sites across Brazil between 2 June 2022 and 2 May 2023, with variables including patient demographics, clinical and tumor characteristics, early treatment history and detailed documentation of palbociclib combination treatment and its outcomes. Palbociclib combinations exhibit favorable effectiveness, as measured by progression-free survival and overall survival rates. Discontinuation rates were low, suggesting that these combinations are well-tolerated in the real-world setting. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusions Approximately 10%–20% of prostate cancers progress to metastatic and castration‐resistant forms (mCRPC). Radioligand (RLT) therapy with [177Lu]Lu‐prostate‐specific membrane antigen (PSMA) is an approved treatment for metastasized mCRPC. Moreover, Actinium‐225 (225Ac), an alpha‐emitter isotope, has also been used to label PSMA and, recently, to treat mCRPC patients with encouraging results. However, robust clinical data on [225Ac]Ac‐PSMA therapy and its comparison with [177Lu]Lu‐PSMA are still limited. Our aim was to evaluate the role of [225Ac]Ac‐PSMA in treating mCRPC and compare it with conventional [177Lu]Lu‐PSMA therapy.A systematic search was performed in PubMed, Web of Science, Scopus and the Cochrane Register of Controlled Trials from June 2023 to January 2024. This work was conducted in accordance with PRISMA guidelines.After screening and study selection according to PRISMA guidelines, 11 studies were included, 9 of which focused on [225Ac]Ac‐PSMA only and two on tandem therapy ([225Ac]Ac‐PSMA/[177Lu]Lu‐PSMA). Overall, the pooled proportion of PSA decline in patients was .85 (95% CI: .79–.91, p < .001); patients pretreated with [177Lu]Lu‐PSMA achieved a pooled proportion of PSA decline of .90 (95% CI: .82–.97, p < .001). In patients treated with tandem therapy, PSA decline was observed in approximately 90% of them, while PSA response rates above 50% ranged from 53.3% to 65%. Xerostomia was the most frequently reported side effect, along with anaemia, thrombocytopenia and nephrotoxicity.Overall, the main results of our study showed that [225Ac]Ac‐PSMA‐617 had a significant therapeutic effect on mCRPC with an acceptable toxicity level. The latter, however, appears greater than with [177Lu]Lu‐PSMA‐617. In future studies, an adequate analysis of the incidence of side effects associated with [225Ac]Ac‐PSMA should be performed to evaluate the role of cumulative toxicity of earlier treatments and the higher frailty of heavily pretreated patients. [ABSTRACT FROM AUTHOR]

Purpose: This study is aimed at investigating the 10‐year outcomes of intraoperative radiotherapy (IORT) in Mexican women with early breast cancer (EBC) treated at the Centro Medico ABC, Mexico City. Methods: A cohort study included women with early‐stage invasive ductal carcinoma aged ≥ 45 years without prior oncologic treatment, tumor size ≤ 3.5 cm, cN0M0, positive hormone receptors, margins ≥ 2 mm, negative sentinel lymph nodes, and no extensive lymphovascular invasion. IORT was administered at 20 Gy for 20–30 min after a lumpectomy. Follow‐up extended over 10 years and included clinical examinations every 6 months for the first 18 months, followed by annual mammograms and conventional examinations. Patients out of the criteria were excluded from this study because they were referred for additional surgery and/or whole‐breast radiation therapy. Results: The study involved 238 patients with an average age of 61.1 years. The mean tumor size was 12 mm, and the percentages of lymphatic invasion, positive hormone receptors, and HER2/neu overexpression were 12.6%, 90.8%, and 2.1%, respectively. The median follow‐up was 66.6 months (range: 1–126 months), and the overall survival and mastectomy‐free rate reached 95.7% and 90%, respectively. Thirteen patients showed side effects; four recurrences were recorded, of which 50% were out‐field relapses. The 5‐year Kaplan–Meier probability of local relapses, mastectomy‐free, and overall survival reached 97.5%, 100%, and 98%, respectively. Conclusions: This is the first 10‐year report about the effect of IORT on Mexican women with EBC in the early stages. Strict adherence to the selection criteria in this study resulted in low rates of side effects, mortality, and local recurrences, demonstrating that IORT is an effective treatment alternative for patients with EBC. Studies with a longer follow‐up period should be performed, as recurrences can occur in the long term. [ABSTRACT FROM AUTHOR]

Background: Clear cell sarcoma (CCS) and alveolar soft part sarcoma (ASPS) are rare, and standard systemic therapy is not established except for sunitinib in ASPS. It is known that CCS and ASPS have a common biological feature of melanoma and Xp11.2/TFE3 translocation renal cell carcinoma, and immune‐checkpoint inhibitors (ICIs) are effective in these tumors. The authors conducted a phase 2 trial to evaluate the efficacy and safety of nivolumab for CCS and ASPS. Methods: The number of patients expected to be enrolled was 15–25 and was determined based on the Bayesian design. The primary end point was the confirmed objective response rate (ORR) according to the central review and the secondary end points included ORR, progression‐free survival (PFS), overall survival (OS), and safety. Results: A total of 26 patients (CCS, 12; ASPS, 14) were enrolled. Efficacy and safety were analyzed on 25 and 26 patients, respectively. The minimum number of responses required for a positive conclusion regarding the efficacy was four. However, only one patient (4.0%) with ASPS had a partial response. Complete response, stable disease, progression disease, and not evaluable were 0%, 60%, 32%, and 4.0%, respectively. Adverse events of grade 3 or 4 occurred in 57.7% (15 of 26). The median PFS was 4.9 months (95% confidence interval [CI], 3.7–8.6 months) and the median OS was 15.8 months (95% CI, 8.2–not reached). Conclusions: The primary end point of the ORR was not met for CCS and ASPS on the central review. Further studies are needed to evaluate ICIs in patients with ASPS. This study evaluated the efficacy and safety of nivolumab monotherapy for patients with clear cell sarcoma and alveolar soft part sarcoma in a single‐arm phase 2 trial. The results showed no clinical efficacy among patients with clear cell sarcoma, whereas further investigation was considered necessary among patients with alveolar soft part sarcoma. [ABSTRACT FROM AUTHOR]

Background: Despite the rise in gender‐affirming care, our understanding of prostate cancer (PCa) in transgender women (TGW) remains in its infancy. Health disparities and lack of PCa awareness and screening are possible barriers to providing quality care for this population. In addition, the implication of hormonal manipulation for the aggressiveness of PCa in TGW is yet to be determined. Here, this study sought to compare oncological characteristics and survival outcomes between transgender and cisgender (CG) patients with PCa via two national data sets. Methods: The Veterans Affairs Informatics and Computing Infrastructure database (1999–2020) and the Surveillance, Epidemiology, and End Results–Medicare database (2010–2017) were reviewed. Demographic and clinical details were analyzed. Logistic regression analysis was performed on propensity score–matched groups to identify predictors of high‐risk disease and metastasis in patients with PCa. Groups were matched 5:1 (CG:TGW) on the basis of age, race, year of diagnosis, and Charlson Comorbidity Index score. Primary outcomes included metastatic presentation, high‐risk localized disease, overall survival (OS), and prostate cancer–specific mortality (PCSM). Results: A total of 1194 patients were included (199 TGW; 995 CG). Associations between transgender identity and metastatic presentation (odds ratio [OR], 0.38; p =.2), high‐risk localized disease (OR, 1.19; p =.50), or PCSM (hazard ratio [HR], 0.65; p =.3) were not detected. Transgender identity was associated with improved OS (HR, 0.67; p =.014). Conclusions: PCa‐specific outcomes seem comparable between TGW and CG men, although the study was underpowered to detect modest differences. Further investigation into the incidence and outcomes of PCa in TGW is warranted. Despite the increasing availability of gender‐affirming care, our understanding of prostate cancer (PCa) in transgender women (TGW) is limited. This study comparing oncological characteristics and survival outcomes between transgender and cisgender patients with PCa suggests comparable outcomes, which indicates the need for further investigation into PCa incidence and outcomes in TGW. [ABSTRACT FROM AUTHOR]

Summary: Aim: This study aims to investigate the predictive factors for conversion therapy in patients with unresectable hepatocellular carcinoma (uHCC) and to evaluate the prognosis of conversion cases by comparing them with partial response (PR) and complete response (CR) cases. Methods: In this retrospective multicentre study, we included a total of 946 uHCC patients treated with atezolizumab and bevacizumab (Atez/Bev) from September 2020 to September 2023. Results: Out of the patients, 43 (4.5%) received conversion therapy following Atez/Bev treatment. The overall response rate was 65.1% and 23.7% in the conversion and non‐conversion group, respectively, with a statistical significance (p < 0.001). Multivariate analyses identified that BCLC stage B or an earlier stage (p = 0.045), absence of macrovascular invasion and extrahepatic spread (p = 0.045), and a low value of neutrophil to lymphocyte ratio (p = 0.04) were significantly favourable predictive factors associated with conversion therapy. The conversion group showed significantly better survival compared to the non‐conversion group (p < 0.001). In the landmark analysis at 6, 12 and 18 months, the conversion group exhibited better survival compared to PR patients in the non‐conversion group (p = 0.04, 0.01 and 0.03, respectively) and there were no significant differences in the overall survival (OS) between the conversion group and patients who achieved a CR (p = 0.7, 1.0 and 0.3, respectively). Conclusions: Patients with low tumour burden and low value of NLR were more likely to undergo conversion therapy. The OS of patients undergoing conversion therapy showed better survival compared to those achieving PR and was comparable to those with CR patients. Conversion therapy could be considered if feasible. [ABSTRACT FROM AUTHOR]

Summary: Background and Aims: The prognostic impact of previous‐HBV‐infection (pHBV) in non‐HBV‐related hepatocellular carcinoma (non‐HBV‐related‐HCC) and the prevalence, characteristics and significance of recently developed high‐sensitivity HBs antigen positivity (hHBsAg+) in these patients remain unclear. We aimed to close these gaps. Methods: We retrospectively screened patients with newly diagnosed non‐HBV‐related‐HCC (standard HBsAg‐test negative) at Hokkaido University. Patients with complete clinical information and preserved serum for hHBsAg+ were included. We evaluated the prevalence, characteristics and prognostic impact of pHBV and hHBsAg+ in non‐HBV‐related‐HCC. Results: A total of 401 non‐HBV‐related‐HCC patients were included (288 with pHBV/113 without pHBV). In non‐HBV‐related‐HCC, pHBV did not affect overall survival (OS). Among non‐HBV‐related‐HCC patients with pHBV, 11.8% (34/288) were hHBsAg+ and had more advanced stages of HCC, higher AFP levels, higher vascular invasion rates, and significantly shorter OS than others (OS: 19.3 vs. 61.4 months, p = 0.012). Comparison of OS among non‐HBV‐related‐HCC patients without pHBV (group 1), those with pHBV and without hHBsAg+ (group 2), and those with pHBV and hHBsAg+ (group 3) revealed significantly shorter OS in group 3 (19.3, 56.6 and 66.4 months in groups 1, 2 and 3, respectively; p = 0.036). Multivariate Cox regression indicated that compared with group 1, only group 3 was significantly and independently associated with shorter OS (HR: 2.044, p = 0.011). Subgroup analysis revealed that this association was particularly evident in non‐HBV‐related‐HCC patients with non‐B‐non‐C aetiology and advanced HCC. Conclusions: In non‐HBV‐related‐HCC patients, hHBsAg+, not pHBV, is significantly and independently associated with poor prognosis. [ABSTRACT FROM AUTHOR]

This study aims to examine the role of elective nodal irradiation (ENI) in clinically node-negative (cN0) sinonasal squamous cell carcinoma (SNSCC) and to define the optimal radiation fields for ENI. We retrospectively reviewed 368 patients with cN0 SNSCC treated between 2009 and 2021. The study evaluated the impact of ENI on overall survival, progression-free survival, regional failure–free survival, and distant metastasis–free survival, along with the coverage areas of ENI. The majority of patients underwent surgery (316/368, 85.9%), with 276 of 368 (75%) having tumors in the maxillary sinus or nasal cavity and 249 of 368 (67.7%) presenting with T4 disease. Additionally, in 119 of the 368 cases (32.3%), tumors were poorly differentiated. The 5-year overall survival, progression-free survival, regional failure–free survival, and distant metastasis–free survival rates were 59.3%, 54.0%, 57.6%, and 58.8%, respectively. ENI was performed in 217 patients (59%), with 16 experiencing neck relapse during follow-up. Although ENI did not enhance survival rates, it significantly reduced the overall regional failure rate (7.9% vs 1.8%; χ2 = 7.98; P <.01) and the cumulative incidence of regional failure (P =.045). Additionally, the subgroups with maxillary sinus origin (2.3% vs 13.5%; P =.025), T4 stage (1.8% vs 8.5%; P =.028), and poor differentiation (2.4% vs 13.5%; P =.029) had higher cumulative incidences of regional failure in patients without ENI. No significant difference was observed in survival and regional failure rates between patients treated with ENI to levels Ib and II with or without level III, as well as between cN0 patients with nonmidline crossing lesions receiving unilateral or bilateral ENI. Despite no survival benefit, ENI significantly decreases the regional failure rate in patients with cN0 SNSCC. For primary lesions not crossing the midline, ipsilateral ENI targeting levels Ib and II proves to be an effective strategy. [ABSTRACT FROM AUTHOR]

Primary soft tissue sarcoma (STS) is rare, with many tumors occurring in extremities. Local management is limb-sparing surgery and preoperative/postoperative radiation therapy (RT) for patients at high risk of local recurrence. We prospectively investigated late normal tissue toxicity and limb function observed after intensity modulated RT (IMRT) in extremity STS. Patients with extremity STS, age ≥16 years. Two treatment cohorts: IMRT 50 Gy in 25 × 2 Gy fractions (preoperative) or 60/66 Gy in 30/33 × 2 Gy fractions (postoperative). The primary endpoint was the rate of grade ≥2 late soft tissue fibrosis (subcutaneous tissue) at 24 months after IMRT (Radiation Therapy Oncology Group late radiation morbidity scoring). One hundred sixty-eight patients were registered between March 2016 and July 2017. Of those, 159 (95%) received IMRT (106, 67% preoperative RT; and 53, 33% postoperative RT) with a median follow-up of 35.2 months (IQR, 32.9-36.6); 62% men, median age 58 years. Of 111 patients assessable for the primary endpoint at 24 months, 12 (10.8%; 95% CI, 5.7%-18.1%) had grade ≥2 subcutaneous fibrosis. The overall rate at 24 months of Radiation Therapy Oncology Group late skin, bone, and joint toxicity was 7 of 112 (6.3%), 3 of 112 (2.7%), and 10 of 113 (8.8%), respectively, and for Stern's scale edema was 6 of 113 (5.3%). More wound complications were observed with preoperative than postoperative RT (29.2% vs 3.8%). Overall survival at 24 months was 84.6%, and the local recurrence event rate at 24 months was 10%. The rate of grade ≥2 subcutaneous fibrosis at 24 months after IMRT was 10.8%, consistent with other recent trials of IMRT and lower than historically reported rates in patients treated with 3-dimensional conformal RT. This trial provides further evidence for the benefits of IMRT in this patient population. [ABSTRACT FROM AUTHOR]

Early detection of lung nodules is essential for lung cancer screening and improving patient survival rates. Traditional object detection networks such as YOLO and Faster R-CNN have shown promising results in detecting lung nodules but often lack sufficient integration of extracted features to enhance accuracy and efficiency. Moreover, these methods typically do not retain the spatial information of lung nodules from the original CT images. To overcome these limitations, a novel lung nodule detection algorithm based on YOLOv7 is introduced. Firstly, to better preserve essential features and minimize interference from irrelevant background noise, a deformable attention module for feature fusion has been designed. Additionally, maximum intensity projection is employed to create projection images at various intensities, thereby enriching the spatial background information that is often missing in single CT slices. Thirdly, the WIoU loss function is utilized to replace the original YOLOv7 loss function, aiming to reduce the influence of low-quality samples on the gradient within the dataset. The proposed model was validated using the publicly available LUNA16 dataset and achieved a recall rate of 94.40% and an AP value of 95.39%. These results demonstrate the enhanced precision and efficiency of lung nodule detection. [ABSTRACT FROM AUTHOR]

Purpose: Extent of resection, MGMT promoter methylation status, age, functional level, and residual tumor volume are established prognostic factors for overall survival in glioblastoma patients. Preoperative tumor volume has also been investigated, but the results have been inconclusive. We hypothesized that the surface area and the shape were more representative of the tumor's infiltrative capacities, and thus, the purpose of this study was to assess the prognostic value of tumor size and shape in patients with glioblastoma. Methods: In total, 271 patients with primary, unifocal glioblastoma were included from two centers in Norway and Sweden, respectively. All tumors were automatically segmented on preoperative MRI scans and manually validated. Tumor volume was used as a measurement of size, whereas sphericity index and area-to-volume ratio defined the shape complexity of the tumor. Contact surface area of the tumor was considered a measurement of both size and shape. Multivariable Cox proportional hazards models were used to assess the prognostic value of the respective tumor measurements, with previously established prognostic factors as covariates. Results: There were no associations between preoperative tumor volume and overall survival. Contact surface area (HR = 1.013, p = 0.002) and sphericity index (HR = 2.223, p = 0.001) were both significant independent prognostic factors for survival in the multivariable Cox models. Contact surface area was also associated with MGMT promoter methylation (p = 0.039) and extent of resection (p = 0.017). Conclusion: Tumor shape complexity appears to be an independent prognostic factor in glioblastoma patients and may also be associated with MGMT promoter methylation status and extent of surgical resection. [ABSTRACT FROM AUTHOR]

The incidence and prevalence of neuroendocrine tumours (NETs) are on the rise, but to date, only complete surgical resection is curative. Among the various therapeutic options for metastatic disease, peptide receptor radionuclide therapy (PRRT), linking a radioactive moiety to an octreotide derivative, has been shown to be highly efficacious and a well‐tolerated therapy, improving progression‐free survival and prolonging overall survival. Nevertheless, complete responses are rare, and the current β‐particle emitters have non‐optimal radiobiological properties. A new generation of α‐particle‐emitting radionuclides is being developed, with the advantages of very high energy and a short path length. We survey the most recent developments in this field, summarising the result of currently performed studies in this potentially ground‐breaking novel form of therapy for NETs. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusions From 2007 to 2017, sorafenib was the sole systemic therapy for hepatocellular carcinoma (HCC), but nine new therapies were approved from 2017 to 2022. No studies have yet examined population‐level treatment patterns for HCC since these approvals.For this retrospective cohort, Surveillance, Epidemiology, and End Results (SEER)–Medicare data were used to identify patients who had HCC diagnosed between 2014 and 2019 with claims through 2020. The authors examined patient characteristics, comorbidities, and receipt of local (e.g., transplantation, resection, embolization) and systemic (e.g., sorafenib, lenvatinib, atezolizumab plus bevacizumab) therapies. Cohort characteristics, treatment patterns, and overall survival (OS) were analyzed, and χ2 tests and t‐tests were used to compare treatments between the 2014–2017 and 2018–209 cohorts. Adjusted Cox models were used to compare median OS between treatment groups.Among 11,766 patients (men, 69.2%; White, 76.9%; median age, 71 years), 60.5% received treatment within 1 year, which remained stable over time (2014–2017, 60.4%; 2018–2019, 61.0%; p = .84). The use of local therapy also remained stable (2014–2017, 52.1%; 2018–2019, 52.8%; p = .43), whereas the use of systemic therapy slightly decreased (2014–2017, 17.0%; 2018–2019, 15.2%; p = .01). First‐line systemic treatments shifted significantly, with sorafenib use dropping from 84.5% (2014–2017) to 41.3% (2018–2019). The median OS among patients who received no treatment, systemic therapies first, or local therapies first was 2.2, 12.0, and 23.6 months, respectively. Patients who were diagnosed in 2019 had better OS (hazard ratio [HR], 0.80; 95% confidence interval [CI], 0.74–0.86) as did those who received systemic therapy first (HR, 0.33; 95% CI, 0.18–0.61), but survival was worse for those who received local therapy first (HR, 1.41; 95% CI, 1.08–1.84) compared with those who were diagnosed in 2014.Local therapy patterns remained stable, but novel therapies replaced sorafenib as the preferred first‐line treatment, improving survival. [ABSTRACT FROM AUTHOR]

Keratin 17 (K17) is frequently overexpressed, associated with poor prognosis in various cancers, and contributes to p27 degradation during cancer progression. Using immunohistochemistry, we evaluated K17 and p27 expression and assessed their biological behavior and prognostic significance in 326 colorectal cancers. High K17 expression was associated with poorly differentiated tumors, high pT classification, and lymph node metastases. Low p27 expression was associated with large tumors, high pT classification, lymphovascular invasion, and lymph node metastases. The overall survival of patients with high K17 expression was significantly worse than that of patients with low K17 expression [hazard ratio (HR) = 1.805, 95% confidence interval (CI) 1.169–2.787; p = 0.007]. Patients with low p27 expression showed significantly worse overall survival than those with high p27 expression (HR = 3.082, 95% CI 1.722–5.517; p < 0.001). When combining the results of K17 and p27 expression, the K17highp27low expression group showed the worst overall survival. On the contrary, the K17high/lowp27high group showed the best overall survival (p < 0.001). Therefore, K17highp27low expression is an independent poor prognostic factor in colorectal cancer. Thus, high K17 and low p27 expression correlate with aggressive clinicopathologic behavior and can be used as poor prognostic markers in colorectal cancer. [ABSTRACT FROM AUTHOR]

Aims Methods and results Conclusions Oesophageal adenocarcinoma (EAC) is a glandular or mucinous epithelial malignancy that can show immunohistochemical evidence of neuroendocrine differentiation (NED) and express the hormone serotonin. The objective of this study was to correlate the presence of NED and serotonin with clinicopathological characteristics and patient outcome after neoadjuvant chemoradiation.A retrospective cohort of patients treated between 2002 and 2021 was established and included 218 oesophagectomy specimens with residual tumour. Representative full‐face sections of tumour were stained for synaptophysin, chromogranin‐A and serotonin by immunohistochemistry, and staining results were correlated with disease‐free survival (DFS) and overall survival (OS). In total, 129 (59%) tumours showed evidence of NED, defined as immunohistochemical expression of synaptophysin or chromogranin‐A, while 40 (18%) showed evidence of NED and expressed serotonin. Patients with neuroendocrine‐positive tumours had significantly shorter median OS compared to those with neuroendocrine‐negative tumours (22.5 versus 48.8 months, P = 0.006), but similar median DFS (13.3 versus 17.8 months, P = 0.34). Using Cox regression, the association between NED and OS was significant in univariate [hazard ratio (HR) = 1.68, 95% confidence interval (CI) = 1.16–2.45] and multivariate (HR = 1.65, 95% CI = 1.08–2.52) analysis. Patients with serotonin‐expressing tumours had similar median OS (21.7 versus 25.9 months, P = 0.24) and DFS (7.3 versus 15.6 months, P = 0.12) compared to those with NED but lacking serotonin. Using Cox regression, serotonin expression was associated with reduced OS in univariate (HR = 1.62, 95% CI = 1.06–2.47) but not multivariate (HR = 1.03, 95% CI = 0.64–1.65) analysis.Our findings support NED as independent predictor of OS in EAC after neoadjuvant chemoradiation. While a subset of tumours with NED expressed serotonin, this did not provide additional prognostic information. [ABSTRACT FROM AUTHOR]

The overall survival (OS) improvement after the advent of several novel systemic therapies, designed for treatment of metastatic urothelial carcinoma of the urinary bladder (mUCUB), is not conclusively studied in either contemporary UCUB patients and/or non‐UCUB patients. Within the Surveillance, Epidemiology, and End Results database, contemporary (2017–2020) and historical (2000–2016) systemic therapy‐exposed metastatic UCUB and, subsequently, non‐UCUB patients were identified. Separate Kaplan–Meier and multivariable Cox regression (CRM) analyses first addressed OS in mUCUB and, subsequently, in metastatic non‐UCUB (mn‐UCUB). Of 3443 systemic therapy‐exposed patients, 2725 (79%) harbored mUCUB versus 709 (21%) harbored mn‐UCUB. Of 2725 mUCUB patients, 582 (21%) were contemporary (2017–2020) versus 2143 (79%) were historical (2000–2016). In mUCUB, median OS was 11 months in contemporary versus 8 months in historical patients (Δ = 3 months; p <.0001). After multivariable CRM, contemporary membership status (2017–2020) independently predicted lower overall mortality (OM; hazard ratio [HR] = 0.68, 95% confidence interval [CI] = 0.60–0.76; p <.001). Of 709 mn‐UCUB patients, 167 (24%) were contemporary (2017–2020) and 542 (76%) were historical (2000–2016). In mn‐UCUB, median OS was 8 months in contemporary versus 7 months in historical patients (Δ = 1 month; p =.034). After multivariable CRM, contemporary membership status (2017–2020) was associated with HR of 0.81 (95% CI = 0.66–1.01; p =.06). In conclusion, contemporary systemic therapy‐exposed metastatic patients exhibited better OS in UCUB. However, the magnitude of survival benefit was threefold higher in mUCUB and approximated the survival benefits recorded in prospective randomized trials of novel systemic therapies. [ABSTRACT FROM AUTHOR]

Background: Sarcopenia is a significant predictor of perioperative adverse outcomes for a variety of malignancies and has significant negative effects on surgical and oncology outcomes. The development of sarcopenia is mainly attributed to aging, inactivity, poor nutrition, and decreased testosterone levels, which suggest a poor prognosis after surgery. Therefore, the primary objective of this systematic review and meta-analysis was to determine the effect of sarcopenia on postoperative survival in patients with oral squamous cell carcinoma. Methods: We systematically searched databases including PubMed, Embase, Cochrane Library, Medline and Web of Science from inception to 12 July 2023, to determine the prognostic value of sarcopenia in oral squamous cell carcinoma. The primary outcome was three-year survival, and secondary outcomes were one-year survival, five-year survival, infection and pneumonia within 30 days postoperatively. Original studies comparing postoperative outcomes in patients with sarcopenia and non-sarcopenia for oral squamous cell carcinoma curative therapy were met the eligibility criteria. We used Endnote X9 for the screening process and used RevMan 5.4.1 for our meta-analysis, all results in this study were performed using a random-effects model. QUIPS (Quality in Prognosis Studies) tools and GRADE (Grading of Recommendations, Assessment, Development and Evaluations) were used for risk of bias and quality of evidence assessment. Result: Ten original studies with 50611 patients met the inclusion criteria. Meta-analysis showed that patients with sarcopenia reduced three-year OS after surgery (OR = 0.73, 95% CI = 0.66-0.81, P < 0.00001). The one-year OS (OR = 0.71, 95% CI = 0.67-0.75, P < 0.00001) and five-year OS (OR = 0.60, 95% CI = 0.45-0.79, P = 0.0003) decreased significantly. Patients with sarcopenia had significantly increased 30-day postoperative mortality and an also increased risk of pneumonia (OR = 1.36, 95% CI = 1.24-1.49, P < 0.00001) and surgical site infection (OR = 2.49, 95% CI = 1.06-5.84, P = 0.04). Conclusion: Sarcopenia is associated with reduced survival in patients after curative resection. Meanwhile, 30-day mortality, postoperative pneumonia and surgical site infection were significantly higher than those in nonsarcopenic patients. Sarcopenia as an extremely important factor of postoperative adverse outcomes in OSCC patients need special attention. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/ , identifier CRD42023444424. [ABSTRACT FROM AUTHOR]

Objective: Hec1 is a component of the Ndc80 kinetochore complex and is frequently upregulated in various cancers. However, the clinical significance of Hec1 in cervical cancer remains largely unknown. This study aimed to investigate the expression patterns of Hec1 in cervical cancer and its relationship with the clinicopathological characteristics of patients diagnosed with the disease. Methods: Immunohistochemistry was used to assess the expression of Hec1 in 136 cervical cancer tissue samples and 82 normal cervical tissue samples. The relationship between Hec1 protein expression and the clinicopathological characteristics of cervical cancer patients was analyzed using the Chi-square test. Additionally, the association between Hec1 protein expression and patient survival was examined using Kaplan-Meier survival curves. Independent risk factors affecting the prognosis of cervical cancer patients were analyzed using the Cox proportional hazards regression model. Results: The positive expression rate of Hec1 protein in cervical cancer tissues was 83.82%, significantly higher than the 7.31% in normal cervical tissues. Compared to patients with negative Hec1 expression, those with positive expression exhibited significantly higher FIGO staging, increased lymph node metastasis, greater depth of tumor stromal infiltration, and larger tumor diameter. Multivariable analysis using the Cox proportional hazards regression model indicated that Hec1 positive expression was an independent risk factor for both overall survival (HR = 2.79, 95% CI: 1.65–4.05, p = 0.012) and progression-free survival (HR = 1.81, 95% CI: 1.22-3.18, p = 0.002) in cervical cancer patients. Kaplan-Meier survival curve analysis showed that patients with positive Hec1 expression experienced a lower overall survival (HR: 2.72, 95% CI: 1.15–4.52, p = 0.004) and progression-free survival (HR: 3.12, 95% CI: 1.62–5.03, p = 0.002) when compared to those with negative Hec1 expression. Conclusion: Hec1 is significantly upregulated in cervical cancer tissues and associated with poor prognosis in cervical cancer patients. Therefore, Hec1 could be a novel biomarker, not only for the diagnosis and treatment evaluation of cervical cancer but also as an indicator for predicting the prognosis of cervical cancer patients. [ABSTRACT FROM AUTHOR]

Background: Levels of C-reactive protein (CRP) and alpha-fetoprotein (AFP) in immunotherapy (CRAFITY) scores are associated with the prognosis of patients with hepatocellular carcinoma (HCC). This study aimed to explore the efficacy of lenvatinib and pembrolizumab (Len-P) based on the CRAFITY score. Methods: In this study, 228 patients with HCC who received Len-P in Sun Yat-sen University Cancer Center were included. CRAFITY 0 score was defined as AFP level below 100 ng/ml, CRP level below 1 mg/dl, CRAFITY 1 score was defined as AFP level at least 100 ng/ml or CRP level at least 1 mg/dl. CRAFITY 2 scores were defined as AFP levels exceeding 100 ng/ml and CRP levels exceeding 100 ng/ml. The primary outcome was overall survival (OS). The second outcome was tumor response rate. Results: The survival time of CRAFITY 0 is significantly longer than that of CRAFITY 1 and CRAFITY 2 (p =.044). Univariate analysis showed that largest tumor size (HR = 2.149; 95% CI 1.129 - 4.091; p =.02), lymph node metastasis (HR = 2.012; 95% CI 1.132- 3.579; p =.017), and CRAFITY (HR = 0.372; 95% CI 0.168-0.824; p =.015) were important risk determinants of OS in all patients. The results of multivariate analysis show that CRAFITY score is an independent risk factors for OS (HR = 0.719; 95% CI 0.377-1.374; p =.048). The ORR of CRAFITY 0, 1 and 2 scores were 36.4%, 32% and 27.4%, respectively (p =.556). The ORR of intrahepatic lesions by CRAFITY 0, 1 and 2 were 37.9%, 35%, 30.6% (p =.688). Conclusion: CRAFITY score is a good predictor of prognosis in HCC patients receiving Len-P. [ABSTRACT FROM AUTHOR]

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Introduction: The delays in cancer therapies have the potential to impact disease progression by allowing the unchecked growth and spread of cancer cells. However, the understanding of the association between treatment waiting time and survival outcomes in patients with esophageal cancer (EC) is limited. This study aims to assess the impact of waiting time on survival outcomes among EC patients in Hebei province, which is recognized as one of the high-risk areas for EC in China. Methods: A total of 9,977 non-metastatic EC patients who underwent surgical treatment were identified between 2000 and 2020. The survival outcomes of overall survival (OS) and cancer-specific survival (CSS) were determined using the Kaplan-Meier methodology. Univariate and multivariate Cox regression analysis was employed to evaluate the impact of treatment delays on OS and CSS. Results: The average delay time for initiating EC surgical treatment after diagnosis was 1.31 months (95%CI=1.29–1.34). Patients with a long delay (≥ 3 months) in treatment, comprising 9977 EC patients, exhibited significantly lower rates of 3-, 5-, and 10-year OS and CSS compared to those without any delay in treatment initiation. A long delay in EC treatment independently associated with an elevated risk of all-cause and cancer-cause mortality among various patient subgroups, including males, older individuals, single individuals, low-income patients, residents of nonmetropolitan counties, as well as those diagnosed with poorly differentiated and stage IV EC. Discussion: The long delay of treatment initiation impacts the outcomes of OS and CSS in EC patients. Optimizing treatment timing may enhance life expectancy for individuals diagnosed with EC. [ABSTRACT FROM AUTHOR]

Background: Lung adenocarcinoma (LUAD) accounts for the highest proportion of lung cancers; however, specific biomarkers are lacking for diagnosis, treatment, and prognostic assessment. Cell division cycle-associated 8 (CDCA8) is a cell cycle regulator with elevated expression in various cancers. However, the association between CDCA8 expression and LUAD prognosis remains unclear. Methods: The association between CDCA8 and LUAD prognosis was evaluated based on the The Cancer Genome Atlas (TCGA) dataset, and CDCA8 related functions were determined using gene enrichment and gene ontology analyses. We also analyzed the association between CDCA8 expression and immune cell infiltration. Immunohistochemistry was used to determine the differential expression of CDCA8 in tumors and controls. Finally, we evaluated the differences in the sensitivity of different levels of CDCA8 to different anticancer drugs in LUAD. Results: CDCA8 expression was significantly higher in primary LUAD tumors than in normal tissues (P < 0.001). Moreover, Kaplan–Meier survival analysis demonstrated that high CDCA8 expression predicted poor survival in patients with LUAD (P = 0.006). The receiver operating characteristic (ROC) curves indicated that CDCA8 was an effective guide for the diagnosis of LUAD. Functional annotation indicated that CDCA8 might be involved in functions such as p53 stabilization, nucleotide metabolism, RNA-mediated gene silencing, and the G2/M phase checkpoint. Immune infiltration results suggested that CDCA8 was positively correlated with Th2 cells and Tgd and negatively correlated with Eosinophils and Mast cells (P < 0.01). In addition, elevated expression of CDCA8 may increase the sensitivity of patients to certain anticancer drugs. Conclusions: CDCA8 upregulation is significantly associated with poor survival and immune infiltration in patients with LUAD. Our study suggests that CDCA8 can be used as a biomarker for LUAD prognosis and a reference for personalized medication. [ABSTRACT FROM AUTHOR]

Background: Durvalumab, an anti-PD-L1 immune checkpoint inhibitor, after radio-chemotherapy (RCT) has changed the management of locally advanced non-small cell lung cancer (LA NSCLC). A series of retrospective studies have investigated different cut-off of lymphocyte count (LyC) and neutrophil-to-lymphocyte ratio (NLR) to predict survival in LA NSCLC. None of these studies has validated their threshold in an independent group of patients. We wanted to assess the OS prognostic value of NLR and LyC in patients with LA NSCLC treated by RCT and durvalumab, with threshold determination and their validation in an external cohort. Methods: Patients were enrolled in four institutions between Oct. 2017 and Jan. 2022. Pre durvalumab LyC, neutrophils count (NC) and NLR were collected. To define NLR and LyC cut-off value predicting survival event, time dependent Receiver Operating Characteristics (ROC) curves was performed. Survival outcomes were estimated by the Kaplan-Meier method and differences were compared using univariate and multivariate Cox proportional hazard models. Results: We included 76 patients in the training set and 85 in the test set. The best cut off were 2,94 for NLR and 0,61 G/l for LyC to predict OS in the training set. For patients with NLR > 2,94, univariate analysis showed no significant deterioration in OS in either the training set (p = 0,066) or the test set (p = 0,12). Patients with LyC > 0,61 G/L, in univariate analysis, had longer OS in training set (p = 0,030) and in test set (p = 0,0062). This OS increase was not found in multivariate analysis (p = 0,057) in training set but was confirmed in test set (0,039). Conclusion: LyC > 0,61 G/l is associated with longer OS for LA NSCLC patient's treated with RCT and durvalumab in univariate analysis. In this context, a particular expectation for organs at risk sparing during RT to avoid lymphopenia seems important. Trial registration: Retrospectively registered. [ABSTRACT FROM AUTHOR]

Aims: We analysed the survival, complications, and function of frozen autograft augmented with intramedullary cement and bridging plates fixation for intercalary bone defect reconstruction in primary bone sarcomas. Patients and Methods: A retrospective cohort study was conducted on 72 patients with primary bone sarcomas (34 males, 38 females) between January 2016 and June 2023. The average age was 22.0 ± 13.6 years (6 to 61 years) and the pathological type included osteosarcoma (55), followed by adamantinoma (5), Ewing's sarcoma (4), undifferentiated pleomorphic sarcoma (4), chondrosarcoma (3), and malignant tenosynovial giant cell tumor (1). The oncological outcomes included local control, metastasis, progression-free survival and overall survival. The functional outcomes were evaluated by the Musculoskeletal Tumor Society Score (MSTS-93), the Toronto Extremity Salvage Score (TESS), and the motion of the joint. Results: The mean follow-up time was 50.0 ± 27.4 months (12 to 99 months). 10 patients died of the disease, 9 patients were alive with disease and 53 patients were alive with no evidence of disease. The average 5-year overall survival of autograft was 85.8% (95% CI, 72.1-93.1%). The average MSTS-93 score was 96% (67–100%) and the average TESS score was 98% (74–100%). Twenty-four patients (33.3%) had at least one complication in the follow-up period. The most common complications were nonunion (9.7%, 7/72) and local recurrence (9.7%, 7/72), followed by leg length discrepancy (6.9%, 5/72), infection (5.6%, 4/72), implant failure (4.2%, 3/72), delayed union (2.8%, 2/72), and graft fractures (1.4%, 1/72). Tumor site was an independent risk factor for bone nonunion (OR, 22.23; p = 0.006). Conclusions: We presented a large technique series for preventing autograft-related complications (especially for autograft fractures) of intercalary frozen autograft reconstruction. This method showed promising functional outcomes and provided durable reconstruction. Level of evidence: level IV therapeutic study. [ABSTRACT FROM AUTHOR]

Current knowledge of tumor biology offers many "targets" for therapeutic intervention. The molecular basis of many processes that play a role in the pathogenesis of colorectal cancer has been identified. One part of colorectal cancer clinical trials is focused on testing substances in a group of patients with tumors in which the TGF-β signalling pathway is hyperactivated. The TGF-β/SMAD signalling pathway members are considered important markers; however, genetic, proteomic, or metabolomic analyses still yield controversial results. According to our results, TGF-βRII, and SMAD4 can be used in monitoring CRC progression. With increasing CRC stage, TGF-βRII expression decreases and SMAD4 expression increases. The patients with TGF-βRII expression lower than 700 pg/ml had a slightly lower survival time (28.103 months) than patients with higher TGF-βRII expression (31.620 months). Conversely, patients with SMAD4 expression lower than 200 pg/ml had a higher survival rate (30.979 months) than patients with higher expression (26.316 months). Regarding TGF-β1 expression, the patient´s survival assessment determined no significant difference between patients with high or low tissue TGF-β1 expression. A personalized approach and consideration of a wide range of factors are important when using these markers in treatment assessment. [ABSTRACT FROM AUTHOR]

Background: Metastatic urothelial carcinoma (mUC) has a poor prognosis, despite recent therapeutic advancements. Prostaglandin Reductase 1 (PTGR1) is essential for activating acylfulvens, a promising class of drugs for treating a subset of urothelial carcinoma (UC) patients. The efficacy of acylfulvens depends on PTGR1 activity and defects in the nucleotide excision repair (NER) pathway, notably ERCC2 mutations present in 10–15% of bladder tumors. This study identifies patients eligible to be included in acylfulven clinical trials based on the presence of PTGR-1 by immunohistochemistry (IHC) staining, RNA expression level and mutations in the NER pathway. Additionally, it evaluates PTGR-1 expression as a prognostic biomarker. Methods: Three PTGR-1 antibodies were tested in a kidney cancer cell line A498 and in tissues with known PTGR1 expression (liver, tonsils, pancreas, small intestine, etc.). Patients with untreated mUC receiving 1st line platinum from Dec. 2019 to Dec. 2021 in the Capital Region, Denmark, were included retrospectively. FFPE tumor samples were collected, and tissue microarrays (TMAs) were constructed. TMAs were stained with the best-performing PTGR1 antibody, RNA expression was analyzed using Nanostring nCounter PanCancer panel and gene mutations were assessed using a targeted genomic panel (TSO-500). Kaplan-Meier and multivariate Cox regression assessed overall survival and covariate impacts. Results: The AB181131 PTGR1 antibody was the most reliable in validation tissues. Tumors from 71 mUC patients were used to construct the TMA, and 40% of tumors scored positive for PTGR1 by IHC staining. A normalized PTGR1 RNA cutoff at 2,550 normalized counts achieved an AUC of 0.9, defining 35 samples as positive with a sensitivity of 96% and specificity of 85% in relation to IHC-positivity. Differential expression showed a significant upregulation of PTGR1 RNA in PTGR1 IHC-positive cases. NER-deficiency and PTGR1 positivity (mutations in ERCC1, ERCC2, ERCC3, ERCC4) was seen in 9 patients (13%). Median overall survival was 16 months in the cohort. Overall survival (OS) analysis indicates that overexpression of PTGR1 RNA was associated with a reduced median OS (12 months vs. 25 months, p = 0.039, log-rank). Conclusion: PTGR1 IHC staining pattern using the Abcam AB181131 antibody is highly correlated with PTGR1 RNA expression. 13% in our cohort were identified as NER deficient and PTGR1 positive. Lower levels of PTGR1 indicates better outcome in this cohort. [ABSTRACT FROM AUTHOR]

There has been limited research into the role of the Pythium insidiosum antigen (PIA) in modulating immune response in patients with pythiosis. This study investigated the balance of T helper type 2 (Th2) and T helper type 1 (Th1) responses after receiving PIA immunotherapy in patients with pythiosis. Next, the phagocytic activity and phagocytic index of IFN-γ primed PIA-treated macrophages were examined. Furthermore, the phagocytosis of infective P. insidiosum zoospores by macrophages was investigated. This work showed that the PIA vaccine induced Th1 response and M1 macrophages in patients with vascular pythiosis who survived and those with localized pythiosis. Phagocytic activity and phagocytic index were increased considerably in localized pythiosis patients compared to vascular pythiosis patients with hematological diseases. IFN-γ priming of PIA-treated macrophages against P. insidiosum zoospores enhanced the phagocytic activity and phagocytic index in vascular and localized pythiosis patients. Macrophages engulfed P. insidiosum zoospores, but the zoospores continued germination, resulting in macrophage death. Overall, our results suggest that PIA can modulate the immune responses, contributing to higher levels of Th1-type cytokine and potentially improving the survival of patients with vascular pythiosis. This study is the first to uncover that P. insidiosum zoospores can survive within macrophages. [ABSTRACT FROM AUTHOR]

Background: The major breakthrough in cancer therapy with immune checkpoint inhibitors (ICIs) has highlighted the important role of immune checkpoints in antitumoral immunity. However, most patients do not achieve durable responses, making biomarker research in this setting essential. CD27 is a well known costimulatory molecule, however the impact of its soluble form in ICI is poorly investigated. Therefore, we aimed at testing circulating concentrations of soluble CD27 (sCD27) and CD27 bound to extracellular vesicles (EVs) as potential biomarkers to predict response and overall survival (OS) in patients undergoing ICI. Methods: Serum and plasma levels of sCD27 were assessed by immunoassay in three patient cohorts (n = 187) with advanced solid malignancies including longitudinal samples (n = 126): a training (n = 84, 210 specimens, Aachen ICI) and validation cohort (n = 70, 70 specimens, Hamburg ICI), both treated with ICI therapy, and a second independent validation cohort (n = 33, 33 specimens, Hamburg non-ICI) undergoing systemic therapy without any ICI. In a subset (n = 36, 36 baseline and 108 longitudinal specimens), EV-bound CD27 from serum was measured, while EV characterization studies were conducted on a fourth cohort (n = 45). Results: In the Aachen and Hamburg ICI cohorts, patients with lower circulating sCD27 levels before and during ICI therapy had a significantly longer progression-free survival (PFS) and OS compared to patients with higher levels, a finding that was confirmed by multivariate analysis (MVA) (Aachen ICI: pPFS = 0.012, pOS = 0.001; Hamburg ICI: pPFS = 0.040, pOS = 0.004) and after randomly splitting both cohorts into training and validation. This phenomenon was not observed in the Hamburg non-ICI cohort, providing a rationale for the predictive biomarker role of sCD27 in immune checkpoint blockade. Remarkably, EV-bound CD27 baseline levels and dynamics during ICI therapy also emerged as potent predictive biomarkers, acting however antagonistically to soluble sCD27, i.e. higher levels were associated with PFS and OS benefit. Combining both molecules ("multi-CD27" score) enhanced the predictive ability (HRPFS: 17.21 with p < 0.001, HROS: 6.47 with p = 0.011). Conclusion: Soluble and EV-bound CD27 appear to have opposing immunomodulatory functions and may represent easily measurable, non-invasive prognostic markers to predict response and survival in patients undergoing ICI therapy. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusions In acute myeloid leukemia (AML), further investigation is warranted to integrate measurable residual disease (MRD) with genetic characteristics for formulating a dynamic prognostic system for predicting response and selecting appropriate postremission therapeutic strategies.The authors incorporated MRD with genetic risk classification and assessed its impact on transplantation decision making within different risk cohorts, comprising 769 patients with newly diagnosed AML across three clinical trials. Only patients who achieved complete remission (CR) within two courses of chemotherapy were selected.In the favorable‐risk and intermediate‐risk groups, patients who underwent transplantation according to the protocol experienced significant 3‐year overall survival (OS) benefits compared with those who did not (favorable‐risk group: hazard ratio [HR], 0.38; 95% confidence interval [CI], 0.20–0.73l p = .004; intermediate‐risk group: HR, 0.53; 95% CI, 0.33–0.85; p = .008). In the intermediate‐risk group, early detection of MRD positivity, even after the initial course of chemotherapy, was associated with a significantly elevated cumulative incidence of relapse (47.2% vs. 36.0%; p = .009) and a notable extension of OS with allogeneic hematopoietic stem cell transplantation (HR, 0.47; 95% CI, 0.28–0.79; p = .004). Conversely, patients who achieved MRD negativity at either of the two time points had comparable OS in the favorable‐risk and intermediate‐risk groups, regardless of whether they underwent transplant or not. In the adverse‐risk group, allogeneic hematopoietic stem cell transplantation led to improvements in OS irrespective of MRD status (HR, 0.51; 95% CI, 0.38–0.69; p < .001).Early clearance of MRD demonstrated significant prognostic value, particularly for patients in the favorable‐risk and intermediate‐risk groups. Positive MRD status after two courses of intensive chemotherapy were associated with a higher relapse rate and inferior OS, necessitating allogeneic hematopoietic stem cell transplantation. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusions Isolated limb infusion and perfusion (ILI/ILP) has been a mainstay treatment for unresectable melanoma in‐transit metastases (ITM), but increased use of immune checkpoint inhibitors (ICI) and intralesional therapy (talimogene laherparepvec [TVEC]) introduced several different management options. This study compares first‐line ILI/ILP, ICI, and TVEC.Retrospective review from 12 international institutions included patients treated from 1990 to 2022 with first‐line ILI/ILP, ICI, or TVEC for unresectable melanoma ITM.A total of 551 patients were treated, with ILI/ILP (n = 356), ICI (n = 125), and TVEC (n = 70) with median follow‐up of 5.5 years. Tumor burden was highest with ILI/ILP and lowest with TVEC (p = .002). Breslow thickness was lowest with TVEC (p = .007). TVEC was mostly used in stage IIIB disease versus IIIC for ILI/ILP and ICI (p = .01). Using ICI as the reference category, TVEC had the highest odds of a complete response (CR) (odds ratio, 1.96; p = .029) and a longer local progression‐free survival (PFS) (hazard ratio [HR], 0.40; p = .003). ILI/ILP had shorter local PFS (HR, 1.72; p = .012), PFS (HR, 1.79; p < .001), distant metastasis‐free survival (DMFS) (HR, 1.75; p = .014), overall survival (HR, 1.82; p = .009), and melanoma‐specific survival (HR, 2.29; p = .004). Stage IIIB disease had longer DMFS (HR, 0.24; p < .001) compared to IIIC/D.TVEC as first‐line therapy for unresectable melanoma ITM was associated with superior CR rates and local PFS. Notably, TVEC was used in patients with a lower Breslow thickness, disease stage, and tumor burden. Therefore, when compared to ILI/ILP and ICI, TVEC should be considered as first‐line therapy for unresectable stage IIIB melanoma ITM with minimal tumor burden and lower Breslow thickness. [ABSTRACT FROM AUTHOR]

ABSTRACT This study compared the safety and efficacy of osimertinib, a third‐generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), with those of other TKIs and its use alongside bevacizumab in patients with EGFR mutation‐positive advanced non–small‐cell lung cancer. PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure, Wanfang, and VIP databases were used to conduct extensive searches for relevant randomized controlled trials until January 30, 2024. Osimertinib monotherapy favored disease control rate, whereas the comparator treatment arm favored overall survival. Using subgroup analysis, the objective response rate and progression‐free survival (PFS) were significantly elevated by Osimertinib monotherapy compared with pemetrexed combined with carboplatin or cisplatin. The comparator treatment arm receiving gefitinib or erlotinib significantly favored progression‐free survival and overall survival compared with osimertinib monotherapy. In patients treated with osimertinib monotherapy, the incidence of all adverse events (AEs) decreased compared with comparator treatment arm. Anemia was the only AE associated with osimertinib monotherapy. Pemetrexed combined with carboplatin or cisplatin resulted in greater loss of appetite than osimertinib monotherapy. The most associated AE of osimertinib monotherapy was diarrhea, according to network analysis. Although its efficacy is not consistent with other EGFR TKIs, osimertinib was associated with a decrease in AEs in patients with EGFR mutation‐positive advanced non–small‐cell lung cancer. [ABSTRACT FROM AUTHOR]

BACKGROUND: The 5-year results of this trial showed that adjuvant therapy with dabrafenib plus trametinib resulted in longer relapse-free survival and distant metastasis-free survival than placebo among patients with BRAF V600-mutated stage III melanoma. Longer-term data were needed, including data regarding overall survival. METHODS: We randomly assigned 870 patients with resected stage III melanoma with BRAF V600 mutations to receive 12 months of dabrafenib (150 mg twice daily) plus trametinib (2 mg once daily) or two matched placebos. Here, we report the final results of this trial, including results for overall survival, melanoma-specific survival, relapse-free survival, and distant metastasis-free survival. RESULTS: The median duration of follow-up was 8.33 years for dabrafenib plus trametinib and 6.87 years for placebo. Kaplan-Meier estimates for overall survival favored dabrafenib plus trametinib over placebo, although the benefit was not significant (hazard ratio for death, 0.80; 95% confidence interval [CI], 0.62 to 1.01; P = 0.06 by stratified log-rank test). A consistent survival benefit was seen across several prespecified subgroups, including the 792 patients with melanoma with a BRAF V600E mutation (hazard ratio for death, 0.75; 95% CI, 0.58 to 0.96). Relapse-free survival favored dabrafenib plus trametinib over placebo (hazard ratio for relapse or death, 0.52; 95% CI, 0.43 to 0.63), as did distant metastasis-free survival (hazard ratio for distant metastasis or death, 0.56; 95% CI, 0.44 to 0.71). No new safety signals were reported, a finding consistent with previous trial reports. CONCLUSIONS: After nearly 10 years of follow-up, adjuvant therapy with dabrafenib plus trametinib was associated with better relapse-free survival and distant metastasis-free survival than placebo among patients with resected stage III melanoma. The analysis of overall survival showed that the risk of death was 20% lower with combination therapy than with placebo, but the benefit was not significant. Among patients with melanoma with a BRAF V600E mutation, the results suggest that the risk of death was 25% lower with combination therapy. [ABSTRACT FROM AUTHOR]

Background: The systemic immune-inflammation index (SII) is an effective tool for predicting the prognosis of patients with cancer. However, its value in patients with locally advanced pancreatic ductal adenocarcinoma (LA-PDAC) undergoing definitive chemoradiotherapy has yet to be addressed. Therefore, we aimed to retrospectively investigate the prognostic significance of the pretreatment SII on the survival outcomes of patients with unresectable LA-PDAC treated with concurrent chemoradiotherapy (C-CRT). Methods: The study included 163 patients with LA-PDAC who had received C-CRT. Using receiver operating characteristic (ROC) curve analysis, the utility of a pre-C-CRT cutoff that could stratify survival results was investigated. The primary and secondary endpoints were the correlations between SII levels and overall survival (OS) and progression-free survival (PFS). Results: At a median follow-up period of 15 months (range: 3.2-94.5), the median OS and PFS rates for the entire group were 15.7 months (95% confidence interval [CI]: 13.4-17.9), and 7.8 months (95% CI: 6.1-9.4), respectively. We divided the patients into 2 SII cohorts based on the ROC curve analysis (area under the curve [AUC]: 71.9%; sensitivity: 68.9%; specificity: 66.7%): SII < 538 (N = 70) and SII ⩾ 538 (N = 93). Comparative survival analysis showed significantly inferior median OS (13.0 vs 25.4 months; P <.001) and PFS (7.0 vs 15.2 months; P =.003) in patients with SII ⩾ 538 compared with those with SII < 538 before treatment. In multivariate analyses, the Eastern Cooperative Oncology Group (ECOG) performance of 2, N1-2 lymph node, CA 19-9 > 90 U/mL, and SII ⩾ 538 status emerged as independent prognosticators of inferior OS and PFS. Conclusions: Present results indicate that patients with unresectable LA-PDAC who underwent C-CRT and had a pretreatment SII ⩾ 538 had significantly worse OS and PFS outcomes compared with those with lower SII values. [ABSTRACT FROM AUTHOR]

Background: The management of Gastroschisis in LMICs continues to be a challenge and is associated with very poor outcomes in contrast with HICs where survival rates near 100%. The purpose of this work is to provide an overview of survival over the past 8 years in a high-flow tertiary centre in Africa. It also investigates the effect of transfer-time and time-to-surgery on outcome. Methods: Retrospective case note review of all GS admissions. The variables assessed were gender, gestational age, weight, type of GS, transfer time, time to surgery and type of surgery. The primary outcome was survival. Results: A total of 171 GS cases were identified: 148 simple, 23 complex. Seven died before surgery. The median age at surgical intervention was 8.5 h (range, 0–48). Closure options ranged from single-staged (primary fascial, skin, umbilical flap and sutureless closure) or a staged (silo) closure. Overall survival was 34.5%. Cases transferred under 8 h had a 46% survival. Surgery under 12 h of life had highest survival, 45%. Simple GS survived better than complex GS (40% vs 10%). Primary closure had a significantly better survival compared to staged closure (51% vs 18%). Conclusions: Transfer-time < 8 h plays a vital role in survival of GS cases. Surgical intervention within 12 h of birth showed a statistically significant improvement in outcome. Primary closure was associated with better survival rates. Level of Evidence: Level III. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to investigate the effects of postoperative complications on long-term survival after laparoscopic surgery for resectable colorectal cancer. Methods: We retrospectively included 204 patients who underwent laparoscopic surgery for colorectal cancer from January 2016 to June 2020. Results: Overall, 68 (33.3%) patients had postoperative complications, twelve (17.6%) of which were classified as Clavien–Dindo class 3a or higher. The 5-year overall survival rate of the non-complication and complication groups were 93.0% and 81.7%, respectively (p = 0.048; Kaplan–Meier analysis and log-rank test), and those among patients with stage III disease were 87.0% and 61.3%, respectively (p = 0.045). The 5-year disease-free survival rates were 85.6% and 77.4%, respectively (p = 0.042). Multivariable Cox proportional-hazards analysis revealed that nodal stage (hazard ratio, 8.392; 95% confidence interval, 1.892–37.175; p = 0.005) was an independent prognostic factor for overall survival, and postoperative complications (hazard ratio, 2.996; 95% confidence interval, 1.076–8.340; p = 0.036) were independent prognostic factors for disease-free survival. Conclusion: Postoperative complications were associated with poor oncological outcomes, especially among patients with stage III colorectal cancer, and independent prognostic factors for disease-free survival. [ABSTRACT FROM AUTHOR]

Background: Postoperative radiotherapy (PORT) is crucial for patients with thoracic locally advanced esophageal squamous cell carcinoma (LA-ESCC, pT3-4aN0-3M0) following esophagectomy. However, the appropriate radiation volume has not been well established. This study aimed to determine the optimal PORT volume for LA-ESCC patients. Methods: LA-ESCC patients post-esophagectomy were randomly assigned to either the large-field irradiation (LFI, primary lesion and lymph node tumor bed plus elective nodal irradiation) group or the small-field irradiation (SFI, primary lesion and lymph node tumor bed alone) group. Stratification was based on T stage and the number of lymph node metastases. The primary endpoint was disease-free survival (DFS), while the secondary endpoints included overall survival (OS), adverse events, and patterns of initial failure. Results: A total of 401 patients were randomly assigned to the intention-to-treat analysis(LFI group, n = 210; SFI group, n = 191). The median DFS of patients in the LFI group was 47.9 months and 48.1 months in the SFI group (HR = 0.87, 95%CI, 0.65 to 1.16; p = 0.32). The estimated one-year and three-year OS rates were 89.2% and 63.2% for patients in the LFI group, compared to 86.6% and 60.7% for the SFI group, respectively. The difference of OS between the two groups was not significant (HR = 0.86, 95%CI, 0.63 to 1.16; p = 0.35). Fewer patients in the LFI group experienced locoregional recurrence compared to the SFI group (12.9% vs 20.4%, p = 0.013). Additionally, locoregional recurrence-free survival of the LFI group was significantly longer than that of SFI group (HR = 0.54, 95%CI, 0.34–0.87; p = 0.01). The most common toxicity was grade 2 esophagitis, observed in 22.9% of the LFI group and 16.8% of the SFI group. Grade 3 adverse events occurred in 6.7% of the LFI group and 2.6% of the SFI group. No grade 4 or 5 toxicities were observed. Adverse events did not significantly differ between the two groups. Conclusions: Postoperative radiotherapy, with the specified radiation volume shows encouraging survival outcomes that are comparable to those of neoadjuvant chemoradiotherapy in patients with thoracic LA-ESCC. Both postoperative irradiation fields were found to be feasible and safe. [ABSTRACT FROM AUTHOR]

Background: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment landscape for non-small cell lung cancer (NSCLC). The variability in patient responses necessitates a blood-based, multi-cohort gene signature to predict ICI response in NSCLC. Methods: We performed transcriptomic profiling of peripheral blood mononuclear cell (PBMC) and buffy coat (BC) samples from three independent cohorts of NSCLC patients treated with ICIs: a retrospective cohort (PMBCR, n = 59), a retrospective validation cohort (BC, n = 44), and a prospective validation cohort (PBMCP, n = 42). We identified a 5-gene signature (UQCRB, NDUFA3, CDKN2D, FMNL1-DT, and APOL3) predictive of ICI response and validated its clinical utility in the prospective PBMCP cohort. Response was evaluated using RECIST criteria, and patients were followed up for progression-free survival (PFS) and overall survival (OS). Results: In the prospective PBMCP cohort, the 5-gene signature demonstrated high accuracy in stratifying patients into responders and non-responders (AUC = 0.89, 95% CI: 0.80–0.99). Predicted responders exhibited significantly longer PFS compared to predicted non-responders (median: 13.8 months vs. 4.2 months, HR = 0.21, 95% CI: 0.07–0.58, p = 0.005). Conclusion: Our study confirms a 5-gene signature as a key biomarker for ICI response in NSCLC, enhancing treatment precision. [ABSTRACT FROM AUTHOR]

Background: A limitation of approved oncolytic viruses is their requirement for intratumoral (i.t.) injection. TILT-123 (igrelimogene litadenorepvec, Ad5/3-E2F-D24-hTNFα-IRES-hIL-2) is a chimeric oncolytic adenovirus suitable for intravenous (i.v.) delivery due to its capsid modification and dual selectivity devices. It is armed with tumor necrosis alpha and interleukin-2 for promoting T-cell activation and lymphocyte trafficking to tumors, thereby enhancing the antitumor immune response. Here, we present the findings after a single i.v. administration of TILT-123 in three phase I dose escalation clinical trials. Methods: Patients with advanced solid tumors initially received a single i.v. dose of TILT-123 ranging from 3 × 109 to 4 × 1012 viral particles (VP). Blood was collected at baseline, 1, 16, and 192 h (7 days) post-treatment for bioavailability and serum analysis. Tumor biopsies were collected prior to treatment and 7 days post-treatment for analysis of viral presence and immunological effects. Patients did not receive any other cancer therapies during this period. Results: Across all three trials (TUNIMO, TUNINTIL, and PROTA), 52 total patients were treated with i.v. TILT-123. Overall, TILT-123 was found to be well-tolerated, with no dose-limiting toxicities observed. Post-treatment tumor biopsies showed expression of viral genes, presence of TILT-123 adenovirus proteins or DNA, and changes in immune cell infiltration from baseline. Increased virus dose did not lead to increased virus detection in tumors. Median overall survival was longer in patients with confirmed presence of TILT-123 in post-treatment biopsies (280 versus 190 days, p = 0.0405). Conclusion: TILT-123 demonstrated safety and significant intratumoral immunomodulation following a single i.v. administration, warranting further investigation. Trial registrations: TUNIMO—NCT04695327. Registered 4 January 2021, https://clinicaltrials.gov/study/NCT04695327. TUNINTIL—NCT04217473. Registered 19 December 2019, https://clinicaltrials.gov/study/NCT04217473. PROTA—NCT05271318. Registered 4 February 2022, https://clinicaltrials.gov/study/NCT05271318. [ABSTRACT FROM AUTHOR]

Introduction: Growth differentiation factor 15 (GDF15) is a cytokine of the TGFβ family. Here, we analyzed GDF15 levels in patients with locally advanced non-small cell lung cancer (LA-NSCLC) who participated in OCOG-ALMERA (NCT02115464), a phase II randomized clinical trial, that investigated metformin in combination with standard of care concurrent chemoradiotherapy (cCRT). OCOG-ALMERA was not able to demonstrate benefit in the metformin arm. Therefore, biomarker studies are needed to better define stratification parameters for future trials. Methods: Patients were randomized to treatment with platinum-based chemotherapy and concurrent chest radiotherapy (60–66 Gy), with or without metformin (2000 mg/d). The trial collected tumor volume parameters, survival outcomes, and patient blood plasma at baseline, during (weeks 1 and 6) and 6 months after cCRT. Plasma GDF15 levels were assayed with the ELISA method. Statistical analyses explored associations between GDF15, survival outcomes, and radiotherapy tumor volumes. Results: Baseline plasma levels of GDF15 were elevated in study patients, they increased during cCRT (p < 0.001), and the addition of metformin was associated with a further increase (week 6, p = 0.033). Baseline GDF15 levels correlated with the radiotherapy gross target volume (GTV, p < 0.01), while week 1 of radiotherapy levels correlated with radiotherapy planned target volume (PTV, p < 0.006). In multivariate analysis, baseline plasma GDF15 was prognostic for poor relapse-free (RFS) and overall survival (OS) (p = 0.005 and p = 0.002, respectively). Conclusions: GDF15 is a plasma marker that responds to the treatment of unresected LA-NSCLC with cCRT and metformin. GDF15 levels correspond with tumor volume and increased GDF15 levels predict for poor RFS and OS. These results require validation in larger clinical trial datasets. Highlights: Analysis of plasma specimens of OCOG-ALMERA, a phase II clinical trial that investigated metformin in combination with standard of care concurrent chemoradiotherapy, suggests that the cytokine growth differentiation factor 15 (GDF15) may be a promising biomarker in unresected locally advanced non-small cell lung cancer (LA-NSCLC). GDF15 levels increased during chemoradiotherapy, did more so in metformin-treated patients and corresponded with the radiotherapy clinical target volumes. Baseline plasma levels of GDF15 predicted overall and relapse-free survival. Validation of these results within larger clinical trials could lead to the establishment of an easily assessable plasma biomarker that could guide LA-NSCLC treatment in the future. [ABSTRACT FROM AUTHOR]

Background: Tyrosine Kinase Inhibitors (TKIs) is an important therapy for patients with oncogene-mutated Non-Small Cell Lung Cancer (NSCLC). However, acquired resistance remains a major challenge. The efficacy of TKIs plus thoracic radiotherapy (RT) in oncogene-mutated NSCLC patients is uncertain. Therefore, we performed a meta-analysis to comprehensively evaluate the efficacy and safety of thoracic RT plus TKIs in oncogene-mutated NSCLC patients. Methods: The following databases were searched for relevant studies: PubMed, EMBASE, and Cochrane Library. Studies comparing the efficacy and safety of TKIs plus RT with TKIs alone in oncogene-mutated NSCLC patients were included in this analysis. Outcomes were median progression-free survival (mPFS), median overall survival (mOS), and incidence of adverse events (AEs). This analysis performed a subgroup analysis of the efficacy of first-line TKIs in combination with RT. Results: This meta-analysis included 12 studies with 2936 patients (n = 823 patients with TKIs plus thoracic RT, n = 2113 patients with TKIs alone). The results showed that patients who received treatment with TKIs plus thoracic RT were associated with superior mPFS and mOS than those who were treated with TKIs alone (hazard ratio [HR]: 0.42, 95% CI 0.30–0.59, p < 0.00001; HR: 0.56, 95% CI 0.41–0.70, p < 0.00001, respectively). Subgroup analyses showed that TKIs plus thoracic RT as first-line treatment was associated with better mPFS and OS (HR: 0.37, 95% CI 0.26–0.52, p < 0.00001; HR: 0.47, 95% CI 0.31–0.70, p = 0.0002, respectively). Although the combination of TKIs with thoracic RT was associated with an increased risk of total AEs (odds ratio [OR]: 1.17, 95% CI 1.06–1.29, P = 0.002), there was no significant difference in serious AEs (grade ≥ 3) (OR: 1.06, 95% CI 0.58–1.92, P = 0.86). The most frequently occurring radiation-related AEs were radiation pneumonitis, radiation esophagitis, and radiation dermatitis, with overall rates of 41.3%, 15.4%, and 11.1%, respectively. The incidence of severe radiation pneumonitis and radiation esophagitis was 4.5% and 6.2%, respectively. Conclusions: In comparison to TKIs alone, TKIs plus thoracic RT are associated with survival benefits, especially as a first-line treatment option. Although TKIs plus thoracic RT may increase the risk of total AEs, it did not increase the risk of severe AEs. Therefore, TKIs plus thoracic RT may be a promising therapeutic regimen for oncogene-mutated NSCLC patients. [ABSTRACT FROM AUTHOR]

Evidence shows that inflammatory responses play an essential role in the development of brain metastases (BM). The goal of this meta-analysis was to critically evaluate the literature regarding the use of the neutrophil to lymphocyte ratio (NLR) to predict the prognosis of patients with BM to help clinicians institute early interventions and improve outcomes. We conducted systematic review and meta-analysis, utilizing data from prominent databases, including PubMed, Cochrane Library and China National Knowledge Infrastructure databases. Our inclusion criteria encompassed studies investigating the studies that assessed the association between NLR and overall survival (OS). We included 11 articles, with 2629 eligible patients, to evaluate the association between NLR and OS. High NLR was significantly associated with shorter OS, with a pooled hazard ratio (HR) of 1.82 (95% CI 1.57–2.11). Subgroup analysis revealed that this association was consistent across different regions, with HRs of 2.03 (95% CI 1.67–2.46) in Asian populations and 1.58 (95% CI 1.35–1.84) in non-Asian populations. Additionally, in a subgroup analysis based on NLR cut-off values, patients with NLR ≥ 3 had an HR of 1.69 (95% CI 1.46–1.96), while those with NLR < 3 had an HR of 2.26 (95% CI 1.64–3.11). Sensitivity analysis confirmed that no single study significantly influenced the pooled effect size. Our meta-analysis confirmed the prognostic value of NLR in patients with brain metastasis. [ABSTRACT FROM AUTHOR]

Objective: Recent evidence suggests that elevated levels of PD-L1 expression may be linked to early resistance to TKI and reduced survival in NSCLC with EGFR mutations. This study aimed to characterize the clinical and molecular features of EGFR-mutated lung adenocarcinomas and determine the prognostic significance associated with high PD-L1 expression. Materials and methods: We conducted a retrospective chart review of 103 consecutive patients with advanced EGFR-mutated NSCLC, who received treatment between 01/01/2016 and 30/12/2020, at our institution. Results: Among the tumors, 17% (n = 18) exhibited high PD-L1 expression (≥50% tumor proportion score), which was associated with a lower prevalence of common EGFR mutations (56% vs. 82%, p = 0.03) and a higher frequency of complex EGFR mutations (28% vs. 7%, p = 0.02). Univariate analysis did not reveal any significant differences in first-line response, progression-free survival, or overall survival between the PD-L1 ≥50% and <50% groups. However, multivariate analysis demonstrated that PD-L1 ≥50% was independently associated with shorter survival (HR = 2.57; 95%CI[1.20–5.55]; p = 0.02), along with male gender (HR = 2.77; 95%CI[1.54–4.19]; p<0.005), presence of liver metastases (HR = 5.80; 95%CI[2.86–11.75]; p<0.005) or brain metastases (HR = 1.99; 95%CI[1.13–3.52]; p = 0.02), and poor general condition at diagnosis (ECOG 3 and 4) (HR = 10.69; 95% CI[4.42–25.85]; p<0.005). Additionally, a trend towards a higher frequency of de novo resistance was observed in the PD-L1 >50% group (7% vs. 17%, p = 0.19). Conclusion: High PD-L1 expression was more commonly found in lung adenocarcinomas with uncommon and complex EGFR mutations. Furthermore, high PD-L1 expression independently predicted poor survival. These findings warrant validation through prospective studies. [ABSTRACT FROM AUTHOR]

Few predictive biomarkers exist for identifying patients who may benefit from neoadjuvant therapy (NAT). The intratumoral microbial composition is comprehensively profiled to predict the efficacy and prognosis of patients with esophageal squamous cell carcinoma (ESCC) who underwent NAT and curative esophagectomy. Least Absolute Shrinkage and Selection Operator (LASSO) regression analysis is conducted to screen for the most closely related microbiota and develop a microbiota‐based risk prediction (MRP) model on the genera of TM7x, Sphingobacterium, and Prevotella. The predictive accuracy and prognostic value of the MRP model across multiple centers are validated. The MRP model demonstrates good predictive accuracy for therapeutic responses in the training, validation, and independent validation sets. The MRP model also predicts disease‐free survival (p = 0.00074 in the internal validation set and p = 0.0017 in the independent validation set) and overall survival (p = 0.00023 in the internal validation set and p = 0.11 in the independent validation set) of patients. The MRP‐plus model basing on MRP, tumor stage, and tumor size can also predict the patients who can benefit from NAT. In conclusion, the developed MRP and MRP‐plus models may function as promising biomarkers and prognostic indicators accessible at the time of diagnosis. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusions Guideline‐concordant care (GCC) is associated with improved survival for patients with cancer; however, variations in receipt of GCC remain a concern. The objective of this study was to evaluate the association of Commission on Cancer (CoC) hospital accreditation status with receipt of GCC and survival among patients with colon cancer.This retrospective observational study identified patients diagnosed with stage I–IV colon cancer from 2018 to 2020 from the National Program of Cancer Registries and Surveillance, Epidemiology, and End Results Program Database. Guideline concordance was defined as receipt of stage‐appropriate lymphadenectomy or chemotherapy. Multivariable logistic regression models investigated associations with receipt of GCC. Cox proportional hazards regression models assessed 3‐year cancer‐specific mortality risk.Of 222,583 patients with colon cancer, 146,629 (91.2%) of eligible patients received guideline‐concordant lymphadenectomy and 70,586 (81.9%) of the eligible patients received guideline‐concordant chemotherapy. Treatment at CoC‐accredited hospitals was the strongest modifiable predictor for receipt of guideline‐concordant lymphadenectomy (odds ratio [OR] 1.82; 95% confidence interval [CI] 1.75–1.88) and chemotherapy (OR 2.14; 95% CI 2.06–2.23). Among patients treated at CoC‐accredited hospitals, risk adjusted mortality was decreased for patients with stage I–II disease (hazard ratio [HR] 0.94; 95% CI 0.80–0.99), stage III disease (HR 0.93; 95% CI 0.88–0.98), and stage IV disease (HR 0.88; 95% CI 0.84–0.92).For patients with colon cancer, treatment at CoC‐accredited hospitals was associated with increased receipt of GCC and decreased mortality risk. Benchmarking data may serve as a valuable accountability tool for quality assessment to improve cancer treatment and outcomes. [ABSTRACT FROM AUTHOR]