High Risk Of Disease Recurrence Research Articles

Occupational exposure to pesticides deregulates systemic cortisol levels in women with breast cancer and correlates with poor prognosis features.

Pesticides have been pointed out as hormone disruptors and may significantly affect the prognosis of hormone-dependent diseases such as breast cancer (BC). Here, we investigated the impact of occupational pesticide exposure on systemic cortisol levels in female rural workers diagnosed with BC. Occupational exposure was assessed by interviews with a standardized questionnaire. Plasma samples (112 from pesticide-exposed women and 77 from unexposed women) were collected in the afternoon, outside the physiological cortisol peak, and analyzed by a chemiluminescent paramagnetic immunoassay for the quantitative determination of cortisol levels in serum and plasma. The results from both groups were categorized according to patients' clinicopathological and exposure data. BC pesticide-exposed women presented higher levels of cortisol than the unexposed. Higher cortisol levels were also detected in the exposed group with more aggressive disease (triple-negative BC), with tumors over 2 cm, with lymph node metastases, and with high risk of disease recurrence and death. These findings demonstrated that there is an association between pesticide exposure and BC that affected cortisol levels and correlated to poor disease prognosis.

TROPION-Breast03: a randomized phase III global trial of datopotamab deruxtecan ± durvalumab in patients with triple-negative breast cancer and residual invasive disease at surgical resection after neoadjuvant therapy.

Despite advances in the treatment of early triple-negative breast cancer (TNBC), patients with residual invasive disease after neoadjuvant therapy have a high risk of disease recurrence and worse survival outcomes than those who have pathological complete response (pCR). Improving outcomes in early TNBC remains an unmet need requiring new adjuvant treatment approaches. Datopotamab deruxtecan (Dato-DXd) is an antibody-drug conjugate comprising a humanized anti-trophoblast cell-surface antigen 2 immunoglobulin G1 (IgG1) monoclonal antibody attached via a plasma-stable, cleavable linker to a potent topoisomerase I inhibitor payload, with activity observed in advanced TNBC. TROPION-Breast03 is an ongoing phase III study evaluating the efficacy and safety of Dato-DXd alone or combined with durvalumab versus standard-of-care therapy as adjuvant treatment in patients with stage I-III TNBC with residual invasive disease at surgical resection following neoadjuvant treatment. Eligible patients, aged ⩾18 years, will be randomized in a 2:1:2 ratio to receive Dato-DXd [6 mg/kg intravenously (IV) every 3 weeks (Q3W); eight cycles] and durvalumab (1120 mg IV Q3W; nine cycles), Dato-DXd monotherapy (6 mg/kg IV Q3W), or investigator's choice of therapy (ICT; capecitabine, pembrolizumab, or capecitabine and pembrolizumab). The primary endpoint is invasive disease-free survival (iDFS) for Dato-DXd and durvalumab versus ICT. Key secondary endpoints include safety, distant disease-free survival, and overall survival for Dato-DXd and durvalumab versus ICT and iDFS for Dato-DXd monotherapy versus ICT. TROPION-Breast03 will be approved by the independent ethics committees or institutional review boards at each study site. All study participants will provide written informed consent. TROPION-Breast03 will help define the potential role of Dato-DXd in the treatment of patients with early-stage TNBC who do not have pCR after neoadjuvant therapy. ClinicalTrials.gov identifier: NCT05629585 (registration date: 29 November 2022).

EPH29 Estimating the Incidence and Characteristics of Female Patients in Norway With Early Breast Cancer Who Are at High Risk of Disease Recurrence

EPH29 Estimating the Incidence and Characteristics of Female Patients in Norway With Early Breast Cancer Who Are at High Risk of Disease Recurrence

A D-Dimer and Thrombin Generation-Based Risk Score Predicts Early-Disease Recurrence in a Prospective Cohort of 1,059 High-Risk Breast Cancer Patients

Introduction: Hemostatic biomarkers have been widely explored in different cancer types as possible predictors of specific cancer outcomes, including survival, malignant disease recurrence, and progression. Results from many small and single-center studies are promising, stimulating confirmatory data from large, prospective studies. In a large cohort of high-risk breast cancer patients enrolled in the prospective, observational, multicenter HYPERCAN study, we aim to establish whether prechemotherapy hemostatic levels can predict disease recurrence (DR). Methods: TheHYPERCAN study (ClinicalTrials.gov ID#NCT02622815) is a prospective, observational, multicenter study, specifically designed to evaluate the role of hemostatic biomarkers in relation to disease recurrence, disease progression, mortality response to therapy and thrombosis. Patients with surgically resected high-risk breast cancer enrolled between 2012 and 2019, from the HYPERCAN study were analyzed. Blood samples collected at enrollment, before starting anticancer treatment, were tested for thrombin generation (TG) by both the ST-Genesia system (STG-ThromboScreen reagent, with and without thrombomodulin) and the calibrated automated thrombogram (CAT) at 5 pM TF. D-dimer, fibrinogen, prothrombin fragment 1+2 (F1+2), and proteins C and free protein S (FPS) were also measured. Outcome analyzed was early-DR (E-DR) within 2 years. Results: A total of 1,059 patients (15M/1,044F), mean age 53 years (SD±11) were analyzed. Breast conserving-resection was performed in 53% and mastectomy in 47% of patients. HER-2 expression was positive in 26% of tumor specimens. The most frequent molecular subtype was Luminal B HER2 negative (32%), followed by Luminal A (22%), Luminal B HER2 positive (19%), Triple negative (13%) and HER2 positive (8%). The largest proportion of tumors were classified as invasive ductal carcinoma, diagnosed in 86% of subjects. All patients were eligible for systemic adjuvant chemotherapy, and for receiving trastuzumab in case of HER-2 positivity. Within 2 years from enrollment, 53 (5.5 %) patients experienced an E-DR, 8 died, while 92 were lost at follow-up. E-DR patients were characterized by worse stage (IIIC), more frequently triple-negative, and less often Luminal-B/HER2-positive molecular subtypes (p<0.05). In addition, E-DR subjects were characterized by increased pre-chemotherapy levels of D-dimer (p=0.004), and peak of TG performed by both Genesia (p=0.001), with and without thrombomodulin, and by CAT (p<0.001) assays. The remaining coagulation parameters were not significantly different between the two groups. The competitive multivariable proportional hazard regression model, corrected for age and surgery status, identified D-dimer and TG peak (by both methods) as independent risk factors for E-DR. This model was internally validated by 1,000-bootstrapping resampling correction. A continuous risk score was therefore generated including D-dimer and TG, which provided a ROC AUC of 0.652 (p<0.001). By this score the patients were significantly stratified in a high- vs low-risk for E-DR (HR 23 vs 0%: Log-rank <0.001). Conclusions: In this large prospective cohort of surgically resected breast cancer patients at high-risk of DR, we could generate and internally validate a risk assessment model based on pre-treatment values of TG and D-dimer, able to identify those subjects at higher risk of DR in the first 2 years after tumor resection. This score, if externally validated, may help the clinical surveillance and serve as treatment guidance in patients with primary breast cancer that are at high risk of recurrence, avoiding overtreatment in those at low risk.

Role of Measurable Residual Disease (MRD) Testing for the Prediction of Late Relapses Following Allogeneic Hematopoietic Cell Transplantation in Adult Acute Myeloid Leukemia

BACKGROUND: Measurable residual disease (MRD) before and/or shortly after allogeneic hematopoietic cell transplantation (HCT) is an independent indicator of high post-HCT relapse risk in acute myeloid leukemia (AML). However, many relapses, particularly among patients with MRD, occur within the first 3 months after allografting, and the role of MRD testing in the identification of patients at risk of relapses occurring at later times is unknown. METHODS: To address this uncertainty, we studied all adults ≥18 years with AML or MDS/AML based on 2022 International Consensus Classification criteria who received a first allograft while in first or second morphologic remission at a single institution between 4/2006 and 3/2023 and underwent MRD testing via multiparameter flow cytometry during the pre-HCT evaluation. In line with the performance characteristics of the assay, any detectable MRD was considered positive. RESULTS: One thousand two hundred and sixty-two patients with AML (n=1,112 [88%]) or MDS/AML (n=150 [12%])underwent allograft following myeloablative (n=732 [58%]) or non-myeloablative (n=530 [42%]) conditioning regimens. Of these, 260 (21%) tested positive for MRD during the pre-HCT evaluation. With a median follow-up of 60.6 (range: 1.9-196.3) months after HCT among survivors, there were 589 deaths, 381 relapses, and 259 NRM events contributing to the probability estimates for relapse, overall survival (OS), relapse-free survival (RFS), and non-relapse mortality (NRM) in this cohort. 239/1,262 patients (19%) experienced disease recurrence (n=181 [14%]) and/or death (n=89 [7%]) within the first 100 days after allografting. Relapse ( P<0.001) and death ( P=0.002) but not NRM ( P=0.29) before day +100 were more common among patients with pre-HCT MRD. Of patients alive without relapse at day +100, 93% (954 of 1,023) underwent bone marrow restaging studies between day 70 and 100 post-HCT. Among these 954 patients, 146 (15%) had MRD before HCT, whereas only 25 (3%) had MRD at day +70-100 testing. The latter had a significantly higher 3-year relapse risk (37% vs. 18%; P=0.002), and worse RFS (17% vs. 68%; P<0.001) OS (16% vs. 72%; P<0.001) and NRM (46% vs. 14%; P<0.001) relative to the 929 patients without MRD; for results of univariate regression models, see Table 1. Importantly, however, while 130 of the 146 patients (89%) with MRD before HCT tested negative for MRD at day +70-100, their outcomes were substantially worse compared to patients who tested negative for MRD before HCT and at day +70-100, with 3-year relapse risk of 38% vs. 15% ( P<0.001), 3-year RFS of 47% vs. 71% ( P<0.001), and 3-year OS of 53% vs. 75% ( P<0.001), whereas 3-year NRM estimates were similar (14% vs. 14% ( P=0.21). Qualitatively similar results were obtained when the cohort was restricted to patients with AML, and also when comparing patients undergoing myeloablative conditioning with those undergoing non-myeloablative conditioning, with a statistically significantly higher relapse risk and lower RFS and OS but not NRM for patients with MRD before HCT but no MRD at day +70-100 compared to those who tested negative for MRD before HCT and at day +70-100 (Table 1). CONCLUSION: For AML and MDS/AML patients alive without relapse at day +100 after allografting, MRD testing at day +70-100 post-HCT identifies patients at increased risk of relapse and worse survival, but only a small number of patients will test positive at this post-HCT timepoint. While a high proportion of patients with MRD before HCT will test negative for MRD at day +70-100, their outcomes are substantially inferior to patients without MRD both before and at day +70-100 after HCT. These data suggest that all patients with pre-HCT MRD should be considered for pre-emptive therapeutic strategies, ideally in the setting of well-controlled clinical trials, given their high risk of disease recurrence regardless of the post-HCT MRD information.

Could a Risk-adapted Approach Support Shared Decision-making Regarding Eligibility for Adjuvant Pembrolizumab for Patients with Clear Cell Renal Cell Carcinoma at High Risk of Recurrence? A Multicentre Cohort Study

The KEYNOTE-564 randomised controlled trial showed a disease-free survival benefit of adjuvant pembrolizumab (aPZB) in comparison to placebo for patients with clear cell renal cell carcinoma (ccRCC) at high risk of recurrence. Despite its recommendation by the European Association of Urology guidelines, the ultimate value of aPZB has recently been questioned. Arguably, patients who might benefit the most from aPZB are those whose probability of RCC recurrence outweighs their probability of dying from other causes over a reasonable timeframe after surgery. To assess the potential impact of this hypothesis on “eligibility” for aPZB, we queried our prospectively collected multi-institutional database for consecutive patients undergoing surgery for nonmetastatic renal masses (cT1–4 N0–1 M0) between 2015 and 2021 to identify ccRCC cases meeting the KEYNOTE-564 criteria. We stratified the patients using the risk-adapted model proposed by Stewart-Merrill et al (whereby stopping follow-up is warranted when the estimated risk of other-cause mortality [OCM] outweighs the estimated risk of RCC recurrence). Then we explored the proportion of patients whose follow-up could theoretically be stopped at 2, 5, 10, or 20 yr, for whom “eligibility” for aPZB might be more controversial. Overall, 1745 patients with ccRCC were included, of whom 419 (24%) met the KEYNOTE-564 criteria. The proportion of patients “not eligible” for aPZB because of higher probability of OCM than of RCC recurrence would have been 81%, 66%, 43%, and 29% at “recommended” follow-up of ≤2.0, ≤5, ≤10, and ≤20 yr, respectively. To the best of our knowledge, this is the first study providing insights to support shared decision-making regarding eligibility for aPZB for patients with nonmetastatic ccRCC with a focus on patient-related factors beyond tumour-driven prognostic scores. Patient summaryAn immunotherapy drug call pembrolizumab given after surgery for nonmetastatic kidney cancer may benefit some patients who have a high risk of disease recurrence, but it can have immune-related side effects. We found that comparing the risk of death from other causes and the risk of cancer recurrence could help in reducing overtreatment of patients who might not benefit from this drug.

Patterns of Recurrence of Cutaneous Melanoma: A Literature Review.

The incidence of melanoma has been dramatically increasing over the last decades. Melanoma is considered to have a high metastatic potential and it can progress via lymphatic vessels or through hematogenous metastasis. Different patterns of recurrence have been described, namely, local, satellite, and in transit metastasis (LCIT), lymphatic metastasis, and systemic metastasis. With a more advanced melanoma stage at diagnosis, there is a higher risk for systemic metastasis in comparison to LCIT; in contrast, early-stage melanoma tends to recur more frequently as LCIT and less commonly as systematic metastasis. The aim of this review was to summarize the patterns of recurrence of cuta-neous melanoma, giving the clinician a practical summary for diagnosis, prognosis, and surveillance. There is a knowledge gap of the common patterns of recurrence that needs to be addressed to better identify patients at high risk of disease recurrence and personalize surveillance strategies as well as patient counseling.

The Role of Cyclin-Dependent Kinases (CDK) 4/6 in the Ovarian Tissue and the Possible Effects of Their Exogenous Inhibition.

The combination of cyclin-dependent kinase (CDK) 4/6 inhibitors with endocrine therapy is the standard treatment for patients with HR+/HER2- advanced breast cancer. Recently, this combination has also entered the early setting as an adjuvant treatment in patients with HR+/HER2- disease at a high risk of disease recurrence following (neo)adjuvant chemotherapy. Despite their current use in clinical practice, limited data on the potential gonadotoxicity of CDK4/6 inhibitors are available. Hence, fully informed treatment decision making by premenopausal patients concerned about the potential development of premature ovarian insufficiency and infertility with the proposed therapy remains difficult. The cell cycle progression of granulosa and cumulus cells is a critical process for ovarian function, especially for ensuring proper follicular growth and acquiring competence. Due to the pharmacological properties of CDK4/6 inhibitors, there could be a potentially negative impact on ovarian function and fertility in women of reproductive age. This review aims to summarize the role of the cyclin D-CDK4 and CDK6 complexes in the ovary and the potential impact of CDK4/6 inhibition on its physiological processes.

Cost-effectiveness analysis of abemaciclib with endocrine therapy (ET) versus ET alone for HR+, HER2-, node-positive, high-risk early breast cancer in Italy.

Abemaciclib was recently approved by the European Medicines Agency in combination with adjuvant endocrine therapy (ET) for adult patients with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-), node-positive early breast cancer (EBC) at high risk of recurrence. To evaluate the cost-effectiveness of abemaciclib plus ET vs. ET alone in patients with HR+, HER2-, node-positive EBC at high risk of disease recurrence, from the Italian healthcare system perspective. A cohort state transition model was developed with five states: invasive disease-free survival (IDFS), nonmetastatic recurrence, remission, metastatic recurrence, and death. The analysis had a time horizon of 30years. Individual patient-level data from the monarchE trial (NCT03155997) were used to generate IDFS estimates. Resource use included drug acquisition/administration, best supportive care, terminal care, adverse events, hospitalization, post-progression therapy, and associated resource use in the metastatic disease health state. Health state utilities were derived from monarchE patient-level data and other sources, applying Italian tariffs where feasible. The estimated total discounted costs (€39,249 vs. €16,806; difference: €22,443) and quality-adjusted life years (QALYs) (11.49 vs. 10.50; difference: 0.99) were higher for abemaciclib plus ET compared with ET alone. The incremental cost-effectiveness ratio was €22,651 per QALY gained. The likelihood of abemaciclib plus ET being cost-effective vs. ET alone was 99% at a willingness-to-pay threshold of €30,000 per QALY gained. Abemaciclib plus ET is a cost-effective treatment option vs. ET alone for those with HR+, HER2- node-positive EBC at high risk of recurrence in Italy.

Molecular Classification of Endometrial Endometrioid Carcinoma With Microcystic Elongated and Fragmented Pattern.

The studies on the molecular classification of endometrioid carcinoma (EC) with microcystic, elongated, and fragmented (MELF) pattern invasion are limited. In this study, 77 cases of ECs with MELF patterns in Chinese women were collected. The molecular classification of the fifth edition of the World Health Organization was used to classify the molecular subtypes using immunohistochemistry staining (mismatch repair [MMR]-immunohistochemistry: MSH2, MSH6, MLH1, and PMS2; p53) and Sanger sequencing targeted POLE . The results showed that the prevalence of the 4 molecular subtypes in EC with MELF pattern was 6.5% (5/77) for POLE mutation, 20.8% (16/77) for MMR deficient, 11.7% (9/77) for p53-mutant, and 61.0% (47/77) for no specific molecular profile. The clinicopathological characteristics of each subtype were compared. The p53-mutant and no specific molecular profile subgroups were associated with higher International Federation of Gynecology and Obstetrics stage and International Federation of Gynecology and Obstetrics grade, deeper myometrial invasion, lymphovascular space invasion, lymph node metastasis, and absence of tumor-infiltrating lymphocytes, whereas the POLE mutation and MMR deficient subgroups were associated with lower aggressive features and prominent tumor-infiltrating lymphocytes. Progression-free survival showed that the p53-mutant and no specific molecular profile subgroups had a poorer prognosis than the POLE mutation and MMR deficient subgroups. However, lymph node metastasis was an independent factor associated with a higher risk of disease recurrence in multivariate analysis. In conclusion, ECs with MELF patterns can be divided into 4 molecular subtypes with discrepancies in aggressive clinicopathological characteristics and tumor-infiltrating lymphocytes. Molecular classification has clinical significance in a morpho-molecular approach for ECs with MELF patterns.

Development and validation of web-based dynamic nomograms predictive of disease-free and overall survival in patients who underwent pneumonectomy for primary lung cancer.

The tumour-node-metastasis (TNM) staging system is insufficient to precisely distinguish the long-term survival of patients who underwent pneumonectomy for primary lung cancer. Therefore, this study sought to identify determinants of disease-free (DFS) and overall survival (OS) for incorporation into web-based dynamic nomograms. The clinicopathological variables, surgical methods and follow-up information of 1,261 consecutive patients who underwent pneumonectomy for primary lung cancer between January 2008 and December 2018 at Sun Yat-sen University Cancer Center were collected. Nomograms for predicting DFS and OS were built based on the significantly independent predictors identified in the training cohort (n = 1,009) and then were tested on the validation cohort (n = 252). The concordance index (C-index) and time-independent area under the receiver-operator characteristic curve (AUC) assessed the nomogram's discrimination accuracy. Decision curve analysis (DCA) was applied to evaluate the clinical utility. During a median follow-up time of 40.5 months, disease recurrence and death were observed in 446 (35.4%) and 665 (52.7%) patients in the whole cohort, respectively. In the training cohort, a higher C-reactive protein to albumin ratio, intrapericardial pulmonary artery ligation, lymph node metastasis, and adjuvant therapy were significantly correlated with a higher risk for disease recurrence; similarly, the independent predictors for worse OS were intrapericardial pulmonary artery and vein ligation, higher T stage, lymph node metastasis, and no adjuvant therapy. In the validation cohort, the integrated DFS and OS nomograms showed well-fitted calibration curves and yielded good discrimination powers with C-index of 0.667 (95% confidence intervals CIs [0.610-0.724]) and 0.697 (95% CIs [0.649-0.745]), respectively. Moreover, the AUCs for 1-year, 3-year, and 5-year DFS were 0.655, 0.726, and 0.735, respectively, and those for 3-year, 5-year, and 10-year OS were 0.741, 0.765, and 0.709, respectively. DCA demonstrated that our nomograms could bring more net benefit than the TNM staging system. Although pneumonectomy for primary lung cancer has brought encouraging long-term outcomes, the constructed prediction models could assist in precisely identifying patients at high risk and developing personalized treatment strategies to further improve survival.

Recent Advancement in the Inhibition of Triple-negative Breast Cancer by N-Heterocycles.

Despite the substantial progress that has been made in cancer therapy over the past few decades, there has been a discernible rise in the number of reported instances of carcinoma over the past few decades. Breast cancer especially triple-negative breast cancer (TNBC), being the most common cancer found in females account for extensive research. This type of cancer, which is responsible for more than 15% to 20% of all breast cancers, is particularly interesting for research since it is difficult to treat due to its poor response to treatment and extremely aggressive nature. In clinical practice, triple-negative breast cancer is characterized by a relatively high risk of disease recurrence and distant metastasis, as well as a poor prognosis regarding overall survival. The goal of this review is to provide the recent advancement of the therapeutic potential of N-heterocycles covering in vitro and in vivo activities for the treatment of triple-negative breast cancer.

System dynamics analysis of mortality post allogeneic hematopoietic stem cell transplant

Allogeneic hematopoietic stem cell transplantation is a well-proven treatment for hematologic malignancies and non-malignancies, but it has a high risk of disease recurrence and severe transplant-related morbidity and death. The mortality and long-term survival of post-allogeneic hematopoietic stem cell transplant patients are improving due to improvements in condition procedures, methods, novel medicines, and supportive care practices. Allogeneic hematopoietic stem cell transplant (allo-HCT) findings, nonetheless, still present a chance for recovery. The results of this investigation updated previous research on risk factors for death following allogeneic HCT. We performed a systematic review and meta-analysis to assess mortality post allo-HCT through a comprehensive literature search using PUBMED/MEDLINE, CINAHL, Web of Science, and EMBASE up to April 30, 2023 and extracted clinical outcome data relating to benefits followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The search identified 551 studies. Only 12 studies (n = 450 patients) met our inclusion criteria. OS rates were the subject of the meta-analysis. The following were the outcomes of heterogeneity tests: According to Chi2=9.14, df=6, P=0.17, and I2=34 percent, the study's data did not appear to be heterogeneous. The OS rate did not differ significantly (P>0.05) using the fixed-effect model analysis. In conclusion, the HSCT must offer the best overall survival, quality of life, and cost outcomes compared to any other treatment strategy. More studies will need a lot of data, and careful data analysis will help get clear data on HSCT outcomes.

Postoperative Early Body Weight Loss Is a Risk Factor for Recurrence in Patients with pStage III Gastric Cancer

Introduction: The goal of this study was to determine whether postoperative early body weight loss (EWL) after radical gastrectomy is a risk factor for recurrence in patients with pathological stage III (pStage III) gastric cancer who received postoperative adjuvant chemotherapy, which included tegafur/gimeracil/oteracil (S-1). Methods: Patients who underwent gastrectomy for gastric cancer were identified from a prospectively managed gastric cancer database. We analyzed 58 consecutive patients who underwent radical gastrectomy with D2 lymph node dissection for confirmed pStage III gastric cancer treated postoperatively with adjuvant chemotherapy including S-1 between 2010 and 2019. Clinical and pathologic characteristics, baseline body mass index (BMI), and postoperative weights were extracted. Weight changes were evaluated from the preoperative period to the start of adjuvant chemotherapy. EWL was defined as % BMI change = (preoperative BMI – postoperative BMI at the start of adjuvant chemotherapy) × 100/preoperative BMI. Results: Of the 58 consecutive patients who underwent radical resection for gastric cancer, 72.4% were male, with a mean age of 65.5 years, and a mean preoperative BMI of 21.2 (range: 15.4–29.1) kg/m². The degree of EWL was found to be closely correlated to compliance with adjuvant chemotherapy. Multivariate analysis by Cox proportional hazard analysis revealed that EWL was an independent factor for relapse-free survival (RFS), and patients with an EWL of 15.9% or more severe had poorer RFS. Conclusion: EWL above a certain rate at the start of adjuvant chemotherapy was a predictor of poor compliance with adjuvant chemotherapy and a high risk of disease recurrence in patients with pStage III gastric cancer.

Efficacy of drug treatment for severe melioidosis and eradication treatment of melioidosis: A systematic review and network meta-analysis.

This systematic review and network meta-analysis (NMA) aimed to compare the efficacy of all available treatments for severe melioidosis in decreasing hospital mortality and to identify eradication therapies with low disease recurrence rates and minimal risk of adverse drug events (AEs). Relevant randomized controlled trials (RCT) were searched from Medline and Scopus databases from their inception until July 31, 2022. RCTs that compared the efficacy between treatment regimens for severe melioidosis or eradication therapy of melioidosis, measured outcomes of in-hospital mortality, disease recurrence, drug discontinuation, or AEs, were included for review. A two-stage NMA with the surface under the cumulative ranking curve (SUCRA) was used to estimate the comparative efficacy of treatment regimens. Fourteen RCTs were included in the review. Ceftazidime plus granulocyte colony-stimulating factor (G-CSF), ceftazidime plus trimethoprim-sulfamethoxazole (TMP-SMX), and cefoperazone-sulbactam plus TMP-SMX had a lower mortality rate than other treatments and were ranked as the top three most appropriate treatments for severe melioidosis with the SUCRA of 79.7%, 66.6%, and 55.7%, respectively. However, these results were not statistically significant. For eradication therapy, treatment with doxycycline monotherapy for 20 weeks was associated with a significantly higher risk of disease recurrence than regimens containing TMP-SMX (i.e.,TMP-SMX for 20 weeks, TMP-SMX plus doxycycline plus chloramphenicol for more than 12 weeks, and TMP-SMX plus doxycycline for more than 12 weeks). According to the SUCRA, TMP-SMX for 20 weeks was ranked as the most efficacious eradication treatment (87.7%) with the lowest chance of drug discontinuation (86.4%), while TMP-SMX for 12 weeks had the lowest risk of AEs (95.6%). Our results found a non-significant benefit of ceftazidime plus G-CSF and ceftazidime plus TMP-SMX over other treatments for severe melioidosis. TMP-SMX for 20 weeks was associated with a lower recurrence rate and minimal risk of adverse drug events compared to other eradication treatments. However, the validity of our NMA may be compromised by the limited number of included studies and discrepancies in certain study parameters. Thus, additional well-designed RCTs are needed to improve the therapy of melioidosis.

Predictors of recurrence following laparoscopic minor hepatectomy for hepatocellular carcinoma in the UK

AimsMinor hepatectomy, which is increasingly carried out laparoscopically (LLR), is a cornerstone of curative treatment for hepatocellular carcinoma (HCC). The majority of relevant publications however originate from regions with endemic viral hepatitis. Although the incidence of HCC in the UK is increasing, little is known about outcomes following LLR. MethodsConsecutive patients undergoing minor (involving ≤2 segments) LLR or open resection (OLR) at our institute between 2014 and 2021 were compared. Selection from a plethora of factors potentially impacting on overall (OS) and disease free survival (DFS) was optimised with Lasso regression. To enable analysis of patients having repeat resection, multivariate frailty modelling was utilised to calculate hazard ratios (HR). ResultsThe analysis of 111 liver resections included 55 LLR and 56 OLR. LLR was associated with a shorter hospital stay (5 ± 2 vs. 7 ± 2 days; p < 0.001) and a lower comprehensive complication index (4.43 vs. 9.96; p = 0.006). Mean OS (52.3 ± 2.3 vs. 49.9 ± 3.0 months) and DFS (33.9 ± 3.4 vs. 36.5 ± 3.6 months; p = 0.59) were comparable between LLR and OLR, respectively (median not reached). Presence of mixed cholangiocarcinoma/HCC, satellite lesions and AFP level predicted OS and DFS. In addition tumour size was predictive of DFS. ConclusionsIn the studied population minor LLR was associated with shorter hospital stay and fewer complications while offering non-inferior long-term outcomes. A number of predictors for disease free survival have been elucidated that may aid in identifying patients with a high risk of disease recurrence and need for further treatment.

PAM50 intrinsic subtypes, risk of recurrence score and breast cancer survival in HIV-positive and HIV-negative patients—a South African cohort study

PurposeTreatment decision making for patients with breast cancer increasingly depends on analysis of markers or systems for estimating risk of breast cancer recurrence. Breast cancer intrinsic subtypes and risk of recurrence (ROR) scores have been found to be valuable in predicting survival and determining optimal treatment for individual patients. We studied the association of breast cancer survival with the PAM50 gene expression assay in HIV-positive and HIV-negative patients.MethodRNA was extracted from formalin-fixed paraffin-embedded specimens of histologically confirmed invasive carcinoma and was purified using the AllPrep® DNA/RNA FFPE kit, Qiagen (Hilden, Germany). The NanoString RUO PAM50 algorithm was used to determine the molecular subtype and the risk of recurrence score of each sample. The overall and disease-free survival were determined with comparison made among HIV-positive and -negative patients. We then generated Kaplan–Meier survival curves, calculated p-values and estimated hazard ratios and their 95% confidence intervals using Cox regression models.ResultsOf the 384 RNA samples analysed, 98.4% met the required RNA quality standard and the specified QC threshold for the test. Luminal B was the most common PAM50 intrinsic subtype and 82.1% of patients were at high risk for disease recurrence based on ROR score. HIV infection, PAM50-based HER2-enriched and basal-like intrinsic subtypes, and high ROR were associated with poor overall and disease-free survival. HIV-positive patients with luminal A & B subtypes had significantly worse survival outcomes than HIV-negative luminal patents.ConclusionAggressive tumour biology was common in our cohort. HIV infection, PAM50 HER2-enriched,basal-like intrinsic subtypes and high ROR score were associated with poor overall and disease-free survival. HIV infection impacted survival in patients with luminal subtypes only.

XRay Vision: A phase 3 study of xevinapant plus radiotherapy (RT) for high-risk, cisplatin-ineligible patients with resected, locally advanced squamous cell carcinoma of the head and neck (LA SCCHN).

TPS6101 Background: The current standard of care for patients with resected LA SCCHN who are at high-risk of disease recurrence and are cisplatin eligible is chemoradiotherapy (CRT; cisplatin + RT). For patients at high risk of disease recurrence who cannot receive cisplatin, treatment options are limited, and there is currently no treatment specifically recommended by international guidelines. Xevinapant is a first-in-class, small-molecule IAP (inhibitor of apoptosis protein) inhibitor that has been shown to restore cancer cell sensitivity to apoptosis, thereby enhancing the effects of chemotherapy and RT. In a randomized phase 2 study in patients with unresected LA SCCHN, treatment with xevinapant + CRT was associated with a 53% lower risk of death after 5 years of follow-up and reduced the risk of death or disease progression by 67% after 3 years of follow-up vs placebo + CRT. In preclinical SCCHN models, xevinapant + RT alone also demonstrated antitumor activity. These promising clinical and preclinical data provide a strong rationale for combining xevinapant and RT in cisplatin-ineligible patients with LA SCCHN. Methods: XRay Vision (NCT05386550) is a randomized, double-blind, placebo-controlled, phase 3 study comparing xevinapant or placebo in combination with intensity-modulated RT (IMRT) in patients with resected LA SCCHN who are ineligible for cisplatin and have a high risk of relapse. Eligible patients must have histologically confirmed cancer of the oral cavity, oropharynx, hypopharynx, or larynx; undergone surgery with curative intent 4 to 8 weeks before the start of treatment; high risk of relapse; no residual disease by computed tomography scan; and ineligible for cisplatin (meeting ≥1 of the following criteria: estimated glomerular filtration rate &lt;60 mL/min/1.73 m2; hearing loss [grade ≥2 audiometric hearing loss or grade ≥2 tinnitus]; grade ≥2 peripheral neuropathy; and if aged ≥70 years old, unfit according to the G8 questionnaire [score ≤14]). Other eligibility criteria include ECOG performance status of 0 or 1 and adequate hematologic and hepatic function. Approximately 700 eligible patients will be randomized to oral xevinapant (200 mg/day on days 1-14 of a 3-week cycle) or placebo for 3 cycles + standard fractionation IMRT (66 Gy in 33 fractions, 2 Gy per fraction, 5 days per week) followed by 3 cycles of xevinapant or placebo. The primary endpoint is disease-free survival. Secondary endpoints include overall survival, time to subsequent cancer treatments, safety, and health-related quality of life. Patients will be followed up for a minimum of 60 months. Enrollment is planned in 27 countries, including the US, and countries in South America, Europe, and Asia. The study started in October 2022, and recruitment is ongoing. Clinical trial information: NCT05386550 .

GS-011 - IMbrave050: Efficacy, safety and patient-reported outcomes (PROs) for adjuvant atezolizumab (atezo) + bevacizumab (bev) vs active surveillance in hepatocellular carcinoma (HCC) patients at high risk of disease recurrence after resection or ablation

GS-011 - IMbrave050: Efficacy, safety and patient-reported outcomes (PROs) for adjuvant atezolizumab (atezo) + bevacizumab (bev) vs active surveillance in hepatocellular carcinoma (HCC) patients at high risk of disease recurrence after resection or ablation

Circulating tumor DNA detection as a prognostic tool in patients with localized colon cancer: A systematic review and meta-analysis.

e15629 Background: Current modalities for postoperative risk stratification in localized colon cancer are still suboptimal in guiding adjuvant chemotherapy (ACT) administration. In recent years, circulating tumor DNA (ctDNA) has emerged as a novel biomarker to identify patients at high-risk for recurrence following R0 tumor resection. In this meta-analysis, we aimed to assess the prognostic value of ctDNA detection on postoperative recurrence risk that in the future, with further study, may help guide ACT treatment. Methods: Electronic databases Pubmed, Google Scholar, and Embase were searched up to 31 January 2023. Patient data were extracted using the following inclusion criteria: stage I to III colon cancers, R0 resection, sufficient ctDNA data following surgery, and no other concurrent malignancy. Pooled relative risk (RR) and 95% confidence interval (CI) were estimated to assess ctDNA positivity on the risk of recurrence in patients having surgery only, patients having surgery followed by ACT, and all patients combined. Random effects model was implemented to account for inter-study variation. Study heterogeneity was detected using χ2 test and I2 coefficient, with I2 more than 50% indicating significant heterogeneity. All analyses were completed using RevMan 5, with p &lt; 0.05 being statistically significance. Results: Fifteen studies with a total of 3411 patients (64.4±10.7 years old) were evaluated. In patients undergoing surgery only without ACT treatment, postoperative ctDNA-positive patients were at higher risk of recurrence compared to those with negative ctDNA (RR = 7.73, 95% CI: 5.73-10.42, p &lt; 0.01, I2= 0%). In patients having surgery followed by ACT, postoperative/pre-ACT ctDNA-positive patients were at higher risk of recurrence compared to ctDNA-negative ones (RR = 5.25, 95% CI: 3.67-7.50, p &lt; 0.01, I2= 19%); post-ACT ctDNA-positive patients were also at higher risk of recurrence (RR = 6.34, 95% CI: 4.12-9.78, p &lt; 0.01, I2= 29%). When combining the two populations (surgery only and surgery followed by ACT), postoperative ctDNA-positive patients again have higher risk of recurrence (RR = 3.86, 95% CI: 2.63-5.67, p &lt; 0.01, I2= 87%); after completing all treatments, ctDNA-positive patients continue to have higher risk of recurrence (RR = 7.02, 95% CI: 3.40-14.51, p &lt; 0.01, I2= 94%). Conclusions: This meta-analysis shows that the presence of ctDNA post-surgery correlates with higher risk of disease recurrence. In localized colon cancers, ctDNA detection can be a valuable tool to identify high-risk patients who, regardless of pathologic stage, may be the most likely to benefit from ACT treatment. Additionally, patients with persistently positive ctDNA after completing ACT are at very high risk for recurrence and should require closer follow-up than current guidelines, along with consideration of enrollment in clinical trials of newer treatment strategies.