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Background: According to long-term follow-up data of malignant tumor patients, assessing treatment effects requires careful consideration of competing risks. The commonly used cause-specific hazard ratio (CHR) and sub-distribution hazard ratio (SHR) are relative indicators and may present challenges in terms of proportional hazards assumption and clinical interpretation. Recently, the restricted mean time lost (RMTL) has been recommended as a supplementary measure for better clinical interpretation. Moreover, for observational study data in epidemiological and clinical settings, due to the influence of confounding factors, covariate adjustment is crucial for determining the causal effect of treatment. Methods: We construct an RMTL estimator after adjusting for covariates based on the inverse probability weighting method, and derive the variance to construct interval estimates based on the large sample properties. We use simulation studies to study the statistical performance of this estimator in various scenarios. In addition, we further consider the changes in treatment effects over time, constructing a dynamic RMTL difference curve and corresponding confidence bands for the curve. Results: The simulation results demonstrate that the adjusted RMTL estimator exhibits smaller biases compared with unadjusted RMTL and provides robust interval estimates in all scenarios. This method was applied to a real-world cervical cancer patient data, revealing improvements in the prognosis of patients with small cell carcinoma of the cervix. The results showed that the protective effect of surgery was significant only in the first 20 months, but the long-term effect was not obvious. Radiotherapy significantly improved patient outcomes during the follow-up period from 17 to 57 months, while radiotherapy combined with chemotherapy significantly improved patient outcomes throughout the entire period. Conclusions: We propose the approach that is easy to interpret and implement for assessing treatment effects in observational competing risk data. [ABSTRACT FROM AUTHOR]

Background: This study aimed to establish a comprehensive clinical prognostic risk model based on pulmonary function tests. This model was intended to guide the evaluation and predictive management of patients with resectable stage I-III non-small cell lung cancer (NSCLC) receiving neoadjuvant chemoimmunotherapy. Methods: Clinical pathological characteristics and prognostic survival data for 175 patients were collected. Univariate and multivariate Cox regression analyses, and least absolute shrinkage and selection operator (LASSO) regression analysis were employed to identify variables and construct corresponding models. These variables were integrated to develop a ridge regression model. The models' discrimination and calibration were evaluated, and the optimal model was chosen following internal validation. Comparative analyses between the risk scores or groups of the optimal model and clinical factors were conducted to explore the potential clinical application value. Results: Univariate regression analysis identified smoking, complete pathologic response (CPR), and major pathologic response (MPR) as protective factors. Conversely, T staging, D-dimer/white blood cell ratio (DWBCR), D-dimer/fibrinogen ratio (DFR), and D-dimer/minute ventilation volume actual ratio (DMVAR) emerged as risk factors. Evaluation of the models confirmed their capability to accurately predict patient prognosis, exhibiting ideal discrimination and calibration, with the ridge regression model being optimal. Survival analysis demonstrated that the disease-free survival (DFS) in the high-risk group (HRG) was significantly shorter than in the low-risk group (LRG) (P=2.57×10-13). The time-dependent receiver operating characteristic (ROC) curve indicated that the area under the curve (AUC) values at 1 year, 2 years, and 3 years were 0.74, 0.81, and 0.79, respectively. Clinical correlation analysis revealed that men with lung squamous cell carcinoma or comorbid chronic obstructive pulmonary disease (COPD) were predominantly in the LRG, suggesting a better prognosis and potentially identifying a beneficiary population for this treatment combination. Conclusion: The prognostic model developed in this study effectively predicts the prognosis of patients with NSCLC receiving neoadjuvant chemoimmunotherapy. It offers valuable predictive insights for clinicians, aiding in developing treatment plans and monitoring disease progression. [ABSTRACT FROM AUTHOR]

Most patients diagnosed with and dying from cancer in Canada are older adults, with aging contributing to the large projected growth in cancer incidence. Older adults with cancer have unique needs, and on a global scale increasing efforts have been made to address recognized gaps in their cancer care. However, in Canada, geriatric oncology remains a new and developing field. There is increasing recognition of the value of geriatric oncology and there is a growing number of healthcare providers interested in developing the field. While there is an increasing number of dedicated programs in geriatric oncology, they remain limited overall. Developing novel methods to delivery geriatric care in the oncology setting and improving visibility is important. Formal incorporation of a geriatric oncology curriculum into training is critical to both improve knowledge and demonstrate its value to healthcare providers. Although a robust group of dedicated researchers exist, increased collaboration is needed to capitalize on existing expertise. Dedicated funding is critical to promoting clinical programs, research, and training new clinicians and leaders in the field. By addressing challenges and capitalizing on opportunities for improvement, Canada can better meet the unique needs of its aging population with cancer and ultimately improve their outcomes. [ABSTRACT FROM AUTHOR]

Simple Summary: Immunotherapy may be beneficial for pancreatic cancer (PC) patients with mismatch repair (MMR) deficiency. Although it is known that MMR deficiency (MMR-D) can result from mutations in MMR genes, the prevalence of these mutations and their impact on the formation of the MMR-D phenotype in PC have been insufficiently researched. Microsatellite instability (MSI) is a hallmark of MMR-D. Here, we estimated the frequency of germline and somatic mutations in the three MMR genes (MLH1, MSH2, and MSH6) in PC patients, estimated the prevalence of MSI, and assessed the relationship between MMR genes mutations and MSI status in PC. In our study of an unselected cohort of PC patients, we identified germline and somatic alterations in MMR genes, however these alterations did not contribute to the MMR-D phenotype. Our findings underscore the necessity of evaluating tumor MMR-D status in PC patients with confirmed Lynch syndrome when deciding whether to administer immunotherapy. Patients with pancreatic cancer (PC) showing mismatch repair (MMR) deficiency may benefit from immunotherapy. Microsatellite instability (MSI) is a hallmark of MMR deficiency (MMR-D). Here, we estimated the prevalence of MSI in PC, investigated germline and somatic mutations in the three MMR genes (MLH1, MSH2, and MSH6), and assessed the relationship between MMR genes mutations and MSI status in PC. Clinical specimens from PC patients were analyzed using targeted next-generation sequencing, including paired normal and tumor specimens from 155 patients, tumor-only specimens from 86 patients, and normal-only specimens from 379 patients. The MSI status of 235 PCs was assessed via PCR. Pathogenic/likely pathogenic (P/LP) germline variants in the MMR genes were identified in 1.1% of patients, while somatic variants were found in 2.6% of patients. No MSI-H tumors were detected. One patient carried two variants (P (VAF = 0.57) and LP (VAF = 0.25)) simultaneously; however, their germline/somatic status remains unknown due to the investigation focusing solely on the tumor and MSI analysis was not performed for this patient. MSI is rare in PC, even in tumors with MMR genes mutations. Our findings underscore the importance of assessing tumor MMR-D status in PC patients with confirmed Lynch syndrome when deciding whether to prescribe immunotherapy. [ABSTRACT FROM AUTHOR]

Background: Prognostic prediction for surgical treatment of gastric cancer remains valuable in clinical practice. This study aimed to develop survival models for postoperative gastric cancer patients. Methods: Eleven thousand seventy-five patients from the Surveillance, Epidemiology, and End Results (SEER) database were included, and 122 patients from the Chinese database were used for external validation. The training cohort was created to create three separate models, including Cox regression, RSF, and DeepSurv, using data from the SEER database split into training and test cohorts with a 7:3 ratio. Test cohort was used to evaluate model performance using cindex, Brier scores, calibration, and the area under the curve (AUC). The new risk stratification based on the best model will be compared with the AJCC stage on the test and Chinese cohorts using decision curve analysis (DCA), the net reclassification index (NRI), and integrated discrimination improvement (IDI). Results: It was discovered that the DeepSurv model predicted postoperative gastric cancer patients' overall survival (OS) with a c-index of 0.787; the area under the curve reached 0.781, 0.798, 0.868 at 1-, 3- and 5- years, respectively; the Brier score was below 0.25 at different time points; showing an advantage over the Cox and RSF models. The results are also validated in the China cohort. The calibration plots demonstrated good agreement between the DeepSurv model's forecast and actual results. The NRI values (test cohort: 0.399, 0.288, 0.267 for 1-, 3- and 5-year OS prediction; China cohort:0.399, 0.288 for 1- and 3-year OS prediction) and IDI (test cohort: 0.188, 0.169, 0.157 for 1-, 3- and 5-year OS prediction; China cohort: 0.189, 0.169 for 1- and 3-year OS prediction) indicated that the risk score stratification performed significantly better than the AJCC staging alone (P < 0.05). DCA showed that the risk score stratification was clinically useful and had better discriminative ability than the AJCC staging. Finally, an interactive native web-based prediction tool was constructed for the survival prediction of patients with postoperative gastric cancer. Conclusion: In this study, a high-performance prediction model for the postoperative prognosis of gastric cancer was developed using DeepSurv, which offers essential benefits for risk stratification and prognosis prediction for each patient. [ABSTRACT FROM AUTHOR]

Background: Patients with nasopharyngeal carcinoma (NPC) undergoing radiotherapy experience significant fatigue, which is frequently underestimated due to the lack of objective indicators for its evaluation. This study aimed to explore the longitudinal association between fatigue and nutrition status 1 week in advance. Methods: From January 2021 to June 2022, a total of 105 NPC patients who received intensity‐modulated radiation therapy were enrolled in the observational longitudinal study. The significant outcomes, including the Piper Fatigue Scale‐12 (PFS‐12), the Scored Patient‐Generated Subjective Global Assessment (PG‐SGA), four body composition indices, and the Hospital Anxiety and Depression Scale (HADS), were assessed weekly from pre‐treatment until the completion of radiotherapy (T0–T7) to explore their relationship. Results: The trajectories of PFS‐12 and all dimensions for 105 participants reached a peak during the fifth week. Sensory fatigue consistently received the highest scores (T0 = 1.60 ± 2.20, T5 = 6.15 ± 1.57), whereas behavior fatigue exhibited the fastest increase over time (T0 = 1.11 ± 1.86, T5 = 5.47 ± 1.70). Higher PG‐SGA scores were found to be weakly explainable for aggravating fatigue (β = 0.02 ~ 0.04). Unlike generalized additive mixed models, marginal structural models (MSM) produced larger effect values (β = 0.12 ~ 0.21). Additionally, body composition indices showed weakly negative relationships with fatigue in MSMs one week in advance. Conclusions: The PG‐SGA may be a more accurate predictor of future‐week fatigue than individual body composition indicators, particularly when HADS is controlled for as a time‐dependent confounder. [ABSTRACT FROM AUTHOR]

Simple Summary: A subset of advanced melanoma patients have a mutant BRAF protein. Two classes of therapy options are available to these patients, but it is unclear which is more effective in this population. We analyzed patient samples treated with either immunotherapy or BRAF-targeted therapy and found that those treated with immunotherapy had notably better outcomes. We further analyzed if aneuploidy or cGAS expression could act as a biomarker for how patients responded to either treatment. We found no association between aneuploidy and clinical outcomes. We observed that cGAS expression may correlate with outcome, but it appears to be a nuanced relationship and requires more study. BRAF-mutant melanoma patients can be treated with targeted therapy or immunotherapies, and it is not clear which should be provided first. Targeted treatments do not work in up to one-third of cases, while immunotherapies may only be effective in up to 60% and come with a high risk of immune-related side effects. Determining which treatment to provide first is thus of critical importance. Recent studies suggest that chromosomal instability and aneuploidy and cyclic GMP-AMP synthase (cGAS) can act as biomarkers for cancer severity and patient outcome. Neither potential biomarker has been extensively studied in melanoma. We examined 20 BRAF-mutant melanomas treated with immunotherapy or targeted therapy and measured chromosomal aneuploidy and cGAS expression levels. Treatment type, aneuploidy, and cGAS expression were correlated with progression-free survival (PFS) in these patients. Those treated with immunotherapy first had significantly better outcomes than those treated with targeted therapy, suggesting immunotherapy should be strongly considered as the first-line therapy for patients bearing BRAF-mutant melanoma. We found that there was no correlation of aneuploidy with outcome while there was some positive correlation of cGAS levels with PFS. Further studies are needed to confirm these findings and to test other potential biomarkers. [ABSTRACT FROM AUTHOR]

Simple Summary: Drugs that help the immune system attack cancer, known as immunotherapy, benefit only a small fraction of patients with cancer that has spread distant from the primary organ. Thus, markers that indicate immunotherapy failure are needed. Overall changes to DNA structure that lead to the gain or loss of extra copies of genes are known as copy number alteration (CNA) burden. In this study, we obtained data on CNA burden, clinical information, and overall tumor mutations, known as tumor mutational burden (TMB), for 1661 patients. These patients were all treated with immunotherapy and had their cancer specimens analyzed by an approved clinical test called MSK-IMPACT. We report that CNA burden could predict those patients who do not benefit from immunotherapy. Additionally, tumors with high CNA but low TMB could identify those with the worst survival. This work can better match patients to their most effective treatment of immunotherapy or other therapies. Immune checkpoint blockade (ICB) benefits only a subset of advanced cancer patients, and predictive biomarkers for immunotherapy response are needed. Recently, copy number alteration (CNA) burden has been proposed to predict ICB resistance. We assessed this finding using the publicly accessible data for 1661 ICB-treated patients whose tumors were profiled by MSK-IMPACT, an approved targeted assay in clinical care. We tested the hypothesis that the continuous increase in CNA burden is associated with poor overall survival following ICB. In addition, we hypothesized that the combinatorial biomarkers of tumor mutational burden (TMB) and CNA burden would better stratify patients for immune status and ICB response. Of the 1661 cases, 79% (n = 1307) were treated with anti PD-1/PD-L1 and the remaining 21% (n = 354) with anti CTLA-4 or the combination of both. In a multivariate analysis, increase in CNA burden was associated with poor overall survival [HR = 1.52, 95% CI (1.01–2.30), p = 0.04]. The combination of biomarkers TMB and CNA burden stratified patients into four clinically distinct subsets among which "LowTMB/HighCNA" showed the worst survival (p < 0.0001). The four patient subsets had unique CNA profiles and enriched pathways, which could predict transcriptional and phenotypic effects related to immune signaling and CD8+ T-cell abundance in the tumor microenvironment. CNA burden was associated with poor overall survival in patients receiving ICB and could improve patient stratification when incorporated with TMB. These findings may guide patient selection for immunotherapy or alternative strategies. [ABSTRACT FROM AUTHOR]

Simple Summary: In clinical practice, human epidermal growth factor receptor (HER2)-negative tumors include triple-negative or luminal breast cancer. HER2-negative breast cancer can be further characterized by immunohistochemical (IHC) and in situ hybridization (ISH) scores into HER2 IHC0 or HER2-low (IHC 1+, 2+/ISH−. Interest in HER2-low tumors has increased as data show the efficacy of HER2-targeted therapies in this subgroup. While several studies have examined treatment variations in the overall breast cancer population, there is limited information on the real-world treatment patterns among patients with HER2 (IHC0/-low) metastatic or recurrent breast cancer. Our study addresses this gap by analyzing treatment and outcomes by HER2 status and found that outcomes were similar in the HER2 IHC0 and -low groups. Our findings add value to the general understanding of the clinical differences between HER2 IHC0/-low and de novo/recurrent disease and have important implications for new effective treatment strategies designed for varying levels of HER2 expression. Improved understanding of the biological heterogeneity of breast cancer (BC) has facilitated the development of more effective and personalized approaches to treatment. This study describes real-world evidence on treatment patterns and outcomes for a population-based cohort of patients with human epidermal growth factor receptor (HER2) IHC0 and -low BC with de novo or recurrent disease from Alberta, Canada. Patients 18+ years old diagnosed with HER2 IHC0/-low, de novo/recurrent BC from 2010 to 2019 were identified using Alberta's cancer registry. Analyses of these patients' existing electronic medical records and administrative claims data were conducted to examine patient characteristics, treatment patterns, and survival outcomes. A total of 3413 patients were included in the study, of which 72.10% initiated first line hormonal and non-hormonal systemic therapy. The 1-year overall survival (OS) was 81.09% [95% CI, 79.52–82.69]. Recurrent patients had a higher OS compared to de novo patients: 54.30 months [95% CI, 47.80–61.90] vs. 31.5 months [95% CI, 28.40–35.90], respectively. Median OS was 43.4 months [95% CI, 40.70–47.10] and 35.80 months [95% CI, 29.00–41.70] among patients with HER2-low and HER2 IHC0 cancer, respectively. The study results provide real-world evidence regarding the clinical outcomes of HER2 IHC0/-low and de novo/recurrent disease. [ABSTRACT FROM AUTHOR]

Background: Gastrointestinal malignancies represent a particularly challenging condition, often requiring a multidisciplinary approach to management in order to meet the unique needs of these individuals and their caregivers. Purpose: In this literature review, we sought to describe care delivery interventions that strive to improve the quality of life and care for patients with a focus on gastrointestinal malignancies. Conclusion: We highlight patient-centered care delivery interventions, including patient-reported outcomes, hospital-at-home interventions, and other models of care for individuals with cancer. By demonstrating the relevance and utility of these different care models for patients with gastrointestinal malignancies, we hope to highlight the importance of developing and testing new interventions to address the unique needs of this population. [ABSTRACT FROM AUTHOR]

Simple Summary: Colorectal cancer (CRC) is the second leading cause of cancer-related death globally. Developing liquid biopsies that aid in the detection and monitoring of recurrent CRC may improve clinical management and patient outcomes. In this study, we investigated a serially sampled blood assay of methylated DNA markers (MDMs) in combination with carcinoembryonic antigen as a clinical tool to surveil and monitor recurrent cancer in a prospective cohort of patients who completed curative-intent therapy for CRC. We demonstrated that the MDMs detected recurrent CRC before the clinical or radiographic detection of recurrence. In a small number of patients, we further showed that the MDMs may correlate with the tumor burden. These data highlight the importance of incorporating epigenetic signatures into liquid biopsies and support further research to validate the correlations of circulating tumor DNA with the tumor burden. Background: Radiographic surveillance of colorectal cancer (CRC) after curative-intent therapy is costly and unreliable. Methylated DNA markers (MDMs) detected primary CRC and metastatic recurrence with high sensitivity and specificity in cross-sectional studies. This study evaluated using serial MDMs to detect recurrence and monitor the treatment response to anti-cancer therapies. Methods: A nested case-control study was drawn from a prospective cohort of patients with CRC who completed curative-intent therapy for CRC of all stages. Plasma MDMs were assayed vis target enrichment long-probe quantitative-amplified signal assays, normalized to B3GALT6, and analyzed in combination with serum carcinoembryonic antigen to yield an MDM score. Clinical information, including treatment and radiographic measurements of the tumor burden, were longitudinally collected. Results: Of the 35 patients, 18 had recurrence and 17 had no evidence of disease during the study period. The MDM score was positive in 16 out of 18 patients who recurred and only 2 of the 17 patients without recurrence. The MDM score detected recurrence in 12 patients preceding clinical or radiographic detection of recurrent CRC by a median of 106 days (range 90–232 days). Conclusions: Plasma MDMs can detect recurrent CRC prior to radiographic detection; this tumor-agnostic liquid biopsy approach may assist cancer surveillance and monitoring. [ABSTRACT FROM AUTHOR]

Background: Immune checkpoint inhibitors (ICIs) are a therapeutic strategy for various cancers although only a subset of patients respond to the therapy. Identifying patients more prone to respond to ICIs may increase the therapeutic benefit and allow studying new approaches for resistant patients. Methods: We analyzed the TCGA cohort of HNSCC patients in relation to their activation of 26 immune gene expression signatures, as well as their cell type composition, in order to define signaling pathways associated with resistance to ICIs. Results were validated on two cohorts of 102 HNSCC patients and 139 HNSCC patients under treatment with PD-L1 inhibitors, respectively, and a cohort of 108 HNSCC HPV negative patients and by in vitro experiments in HNSCC cell lines. Results: We observed a significant association between the gene set and TP53 gene status and OS and PFS of HNSCC patients. Surprisingly, the presence of a TP53 mutation together with another co-driver mutation was associated with significantly higher levels of the immune gene expression, in comparison to tumors in which the TP53 gene was mutated alone. In addition, the higher level of TP53 mutated-dependent MYC signature was associated with lower levels of the immune gene expression signature. In vitro and three different patient cohorts validation analyses corroborated these findings. Conclusions: Immune gene signature sets associated with TP53 status and co-mutations classify with more accuracy HNSCC patients. These biomarkers may be easily implemented in clinical setting. [ABSTRACT FROM AUTHOR]

Objective: Endometrial cancer recurrence is one of the main factors leading to increased mortality, and there is a lack of predictive models. Our study aimed to establish a nomogram predictive model to predict recurrence in endometrial cancer patients. Method: Screen 517 endometrial cancer patients who came to Nanjing Drum Tower Hospital from 2008 to 2018. All these data are listed as the training group, and then 70% and 60% are randomly divided into verification groups 1 and 2. Univariate, Multivariate logistic regression, stepwise regression were used to select variables for nomogram. Nomogram identification and calibration were evaluated by concordance index (c-index), area under receiver operating characteristic curve (AUC) over time and calibration plot Function. By decision curve analysis (DCA), net reclassification index (NRI), integrated discrimination improvement (IDI), we compared and quantified the net benefit of nomogram and ESMO-ESGO-ESTRO model-based prediction of tumor recurrence. Results: A nomogram predictive model of endometrial cancer recurrence was established with the eight variables screened. The c-index (for the training cohort and for the validation cohort) and the time-dependent AUC showed good discriminative power of the nomogram. Calibration plots showed good agreement between nomogram predictions and actual observations in both the training and validation sets. Conclusions: We developed and validated a predictive model of endometrial cancer recurrence to assist clinicians in assessing recurrence in endometrial cancer patients. [ABSTRACT FROM AUTHOR]

Background: In the era of anti-HER2 targeted therapy, the potential clinical feasibility of considering HER2-overexpressing breast cancer cases presenting with 1-3 positive axillary lymph nodes as low-risk, and thereby contemplating postoperative radiotherapy reduction, remains an important subject for in-depth examination. The aim of this retrospective study was to evaluate the effectiveness of de-escalated radiotherapy in T1-2N1M0 HER2-overexpressing breast cancer patients receiving anti-HER2 targeted therapy. Specifically, omitting regional lymph node irradiation (RNI) after breast-conserving surgery and only performing whole-breast irradiation or omitting postmastectomy radiation therapy. Methods: A retrospective analysis was conducted on 429 patients with stage T1-2N1M0 primary invasive HER2-overexpressing breast cancer from our center between 2004 and 2018. Patients who received anti-HER2 targeted therapy were divided into an RNI group and a no RNI group to assess the role of RNI. The prognostic role of RNI was investigated via the Kaplan-Meier method and Cox proportional hazards modeling. Results: The median follow-up time was 46.8 months (range 7.1-225.8 months). In the anti-HER2 targeted therapy group RNI yielded no significant improvements in invasive disease-free survival (IDFS) (p = 0.940), localregional recurrence-free survival (p = 0.380), distant metastases-free survival (p = 0.698), or overall survival (p = 0.403). Estrogen receptor (ER) status (hazard ratio [HR] 0.105, 95% confidence interval [CI] 0.023-0.749, p = 0.004) and lymph vascular invasion status (LVI) (HR 5.721, 95% CI 1.586-20.633, p = 0.008) were identified as independent prognostic factors for IDFS, and ER-positive and LVInegative patients exhibited better prognoses. Conclusion: Omitting RNI may be a safe option in T1-2N1 HER2-overexpressing breast cancer patients receiving standardized anti-HER2 targeted therapy; particularly in ER-positive or LVI-negative subgroups. [ABSTRACT FROM AUTHOR]

Background: BRCA1 and BRCA2 (BRCA1/2) are the most frequently investigated genes among Caucasian pancreatic cancer patients, whereas limited reports are available among Asians. We aimed to investigate the prevalence of BRCA1/2 germline variants in Pakistani pancreatic cancer patients. Methods: One hundred and fifty unselected and prospectively enrolled pancreatic cancer patients were comprehensively screened for BRCA1/2 germline variants using denaturing high-performance liquid chromatography and high-resolution melting analyses, followed by DNA sequencing of the variant fragments. The novel variants were analyzed for their pathogenic effect using in-silico tools. Potentially functional variants were further screened in 200 cancer-free controls. Results: Protein truncating variant was detected in BRCA2 only, with a prevalence of 0.7% (1/150). A frameshift BRCA2 variant (p.Asp946Ilefs*14) was identified in a 71-year-old male patient of Pathan ethnicity, with a family history of abdominal cancer. Additionally, we found a novel variant in BRCA2 (p.Glu2650Gln), two previously reported variants in BRCA1 (p.Thr293Ser) and BRCA2 (p.Ile2296Leu) and a recurrent nonsense variant in BRCA2 (p.Lys3326Ter). These variants were classified as variants of uncertain significance (VUS). It is noteworthy that none of these VUS carriers had a family history of pancreatic or other cancers. Conclusions: In this first study, BRCA1/2 pathogenic variant is identified with a low frequency in pancreatic cancer patients from Pakistan. Comprehensive multigene panel testing is recommended in the Pakistani pancreatic cancer patients to enhance genetic understanding in this population. [ABSTRACT FROM AUTHOR]

We examined the role of receptor profiles and other prognostic factors in survival outcomes after stereotactic radiosurgery (SRS) for brain metastases in breast cancer patients, to help improve selection of candidates for SRS. We included 149 consecutive patients who received SRS between 2012 and 2019 at the University Hospital of Copenhagen, Rigshospitalet, Denmark. Overall survival (OS) following SRS was determined through the Kaplan–Meier method, while CNS progression-free survival (CNS-PFS) was determined through competing risk analysis. Prognostic factors for both OS and CNS-PFS were evaluated through uni- and multivariate Cox regression and Fine-Gray models, respectively. The proportional hazards assumptions were tested through Schoenfeld residuals, and non-proportionality was accounted for by the inclusion of time-dependent variables. Median OS was 14.8 months for the entire cohort and was as follows for the four receptor profiles: 33.3 months for ER+/HER2+ (ER: estrogen receptor, HER2: human epidermal growth factor receptor 2), 11.0 months for ER+/HER2−, 17.7 months for ER−/HER2+, and 5.3 months for ER−/HER2−. In the multivariate model, the ER−/HER2− receptor profile (hazard ratio (HR): 2.00, 95% confidence interval (CI): 1.09–3.67) and the presence of extracranial visceral metastases (HR: 2.90, 95% CI: 1.53–5.50) were associated with worse OS. The ER+/HER2+ receptor profile (HR: 0.43, 95% CI: 0.19–0.96) and 5+ lines of treatment (HR: 0.40, 95% CI: 0.20–0.82) were both associated with improved OS. For CNS-PFS, 5+ lines of treatment (sub-distributional hazard ratio (SHR): 2.88, 95% CI: 1.06–7.81) was associated with worse CNS-PFS, while extracranial visceral metastases (SHR: 0.54, 95% CI: 0.30–0.97) was associated with reduced risk of CNS progression – which is primarily due to patients with extracranial metastases dying before developing new CNS progression. Extracranial visceral disease and the ER−/HER2− receptor profile were associated with poor survival outcomes following SRS. [ABSTRACT FROM AUTHOR]

Background: In 2020 Globocan reported nearly 1.4 million new cases of gynaecology cancer worldwide. Cancer related fatigue has been identified as a symptom that can be present for gynaecology cancer patients many years after treatment. The current evidence around the management of this symptom suggests that exercise has the most positive outcome. However, some ambiguity remains around the evidence and whether it can address all areas of fatigue effectively. More recently, other interventions such as mindfulness have begun to show a favourable response to the management of symptoms for cancer patients. To date there has been little research that explores the feasibility of using both these interventions together in a gynaecology cancer population. This study aims to explore the feasibility of delivering an intervention that involves mindfulness and mindfulness and exercise and will explore the effect of this on fatigue, sleep, mood and quality of life. Methods/Design: This randomised control trial will assess the interventions outcomes using a pre and post design and will also include a qualitative process evaluation. Participants will be randomised into one of 2 groups. One group will undertake mindfulness only and the other group will complete exercise and mindfulness. Both groups will use a mobile application to complete these interventions over 8 weeks. The mobile app will be tailored to reflect the group the participants have drawn during randomisation. Self-reported questionnaire data will be assessed at baseline prior to commencing intervention and at post intervention. Feasibility will be assessed through recruitment, adherence, retention and attrition. Acceptability and participant perspective of participation (process evaluation), will be explored using focus groups. Discussion: This trial will hope to evidence and demonstrate that combination of two interventions such as mindfulness and exercise will further improve outcomes of fatigue and wellbeing in gynaecology cancer. The results of this study will be used to assess (i) the feasibility to deliver this type of intervention to this population of cancer patients using a digital platform; (ii) assist this group of women diagnosed with cancer to manage fatigue and other symptoms of sleep, mood and impact their quality of life. Trial registration: NCT05561413. [ABSTRACT FROM AUTHOR]

Simple Summary: This study developed an interpretable scoring system using artificial intelligence and bladder tissue images. It identified two distinct risk groups with different outcomes in high-grade bladder cancer. The scoring system was associated with various molecular features and gene mutations. This system can save shared clinical decision making and cost by identifying patients who need further molecular testing. Muscle-invasive bladder cancer (MIBC) is a highly heterogeneous and costly disease with significant morbidity and mortality. Understanding tumor histopathology leads to tailored therapies and improved outcomes. In this study, we employed a weakly supervised learning and neural architecture search to develop a data-driven scoring system. This system aimed to capture prognostic histopathological patterns observed in H&E-stained whole-slide images. We constructed and externally validated our scoring system using multi-institutional datasets with 653 whole-slide images. Additionally, we explored the association between our scoring system, seven histopathological features, and 126 molecular signatures. Through our analysis, we identified two distinct risk groups with varying prognoses, reflecting inherent differences in histopathological and molecular subtypes. The adjusted hazard ratio for overall mortality was 1.46 (95% CI 1.05–2.02; z: 2.23; p = 0.03), thus identifying two prognostic subgroups in high-grade MIBC. Furthermore, we observed an association between our novel digital biomarker and the squamous phenotype, subtypes of miRNA, mRNA, long non-coding RNA, DNA hypomethylation, and several gene mutations, including FGFR3 in MIBC. Our findings underscore the risk of confounding bias when reducing the complex biological and clinical behavior of tumors to a single mutation. Histopathological changes can only be fully captured through comprehensive multi-omics profiles. The introduction of our scoring system has the potential to enhance daily clinical decision making for MIBC. It facilitates shared decision making by offering comprehensive and precise risk stratification, treatment planning, and cost-effective preselection for expensive molecular characterization. [ABSTRACT FROM AUTHOR]

Source Citation: Schrag D, Uno H, Rosovsky R, et al; CANVAS Investigators. Direct oral anticoagulants vs low-molecular-weight heparin and recurrent VTE in patients with cancer: a randomized clinical trial. JAMA. 2023;329:1924-1933. 37266947 Clinical Impact Ratings: GIM/FP/GP: Hospitalists: Oncology: Hematology: [ABSTRACT FROM AUTHOR]

Purpose: We developed a nomogram to predict 3-year, 5-year and 7-year cancer survival rates of cancer patients. Methods: This prospective cohort study included 20,491 surviving patients first diagnosed with cancer in Guangzhou from 2010 to 2019. They were divided into a training and a validation group. Lifestyle, clinical and histological parameters (LCH) were included in multivariable Cox regression. Akaike information criterion was used to select prediction factors for the nomogram. The discrimination and calibration of models were assessed by concordance index (C-index), area under time-dependent receiver operating characteristic curve (time-dependent AUC), and calibration plots. We used net reclassification index (NRI) and integrated discrimination improvement (IDI) to compare the clinical utility of LCH prediction model with the prediction model based on lifestyle factors (LF). Results: 13 prediction factors including age, sex, BMI, smoking status, physical activity, sleep duration, regular diet, tumor grading, TNM stage, multiple primary cancer and anatomical site were included in the LCH model. The LCH model showed satisfactory discrimination and calibration (C-index = 0.81 (95% CI 0.80–0.82) for training group and 0.80 (0.79–0.81) for validation group, both time-dependent AUC > 0.70). The LF model including smoking status, physical activity, sleep duration, regular diet, and BMI showed less satisfactory discrimination (C-index = 0.60 (95% CI 0.59–0.61) for training and 0.60 (0.58–0.62) for validation group). The LCH model had better accuracy and discriminative ability than the LF model, as indicated by positive NRI and IDI values. Conclusions: The LCH model shows good accuracy, clinical utility and precise prognosis prediction, and may serve as a tool to predict cancer survival of cancer patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Depression and cognitive problems are common in breast cancer survivorship and reduce quality of life. Depression, a risk factor for cognitive decline, is often accompanied by elevated inflammation and a "leaky gut", which can also impact cognitive function. This study assessed whether depression in tandem with either elevated inflammation or intestinal permeability predicted poorer subjective or objective cognitive function among breast cancer survivors. In secondary analyses of data from 613 survivors with 1015 total study visits, we found that depression combined with either heightened inflammation or intestinal permeability enhanced subjective cognitive complaints, especially focus problems. On neuropsychological tests, depressed survivors performed worse regardless of inflammation or intestinal permeability. These findings suggest that survivors with depression accompanied by immune dysregulation may be more aware of depression-related cognitive deficits compared to other depressed survivors. About one-in-three breast cancer survivors have lingering cognitive complaints and objective cognitive impairment. Chronic inflammation and intestinal permeability (i.e., leaky gut), two risk factors for cognitive decline, can also fuel depression—another vulnerability for cognitive decline. The current study tested whether depression accompanied by high levels of inflammation or intestinal permeability predicted lower subjective and objective cognitive function in breast cancer survivors. We combined data from four breast cancer survivor studies (n = 613); some had repeated measurements for a total of 1015 study visits. All participants had a blood draw to obtain baseline measures of lipopolysaccharide binding protein—a measure of intestinal permeability, as well as three inflammatory markers that were incorporated into an inflammatory index: C-reactive protein, interleukin-6, and tumor necrosis factor-α. They reported depressive symptoms on the Center for Epidemiological Studies depression scale (CES-D), and a binary variable indicated clinically significant depressive symptoms (CES-D ≥ 16). The Kohli (749 observations) and the Breast Cancer Prevention Trial (591 observations) scales assessed subjective cognitive function. Objective cognitive function tests included the trail-making test, Hopkins verbal learning test, Conners continuous performance test, n-back test, FAS test, and animal-naming test (239–246 observations). Adjusting for education, age, BMI, cancer treatment type, time since treatment, study visit, and fatigue, women who had clinically elevated depressive symptoms accompanied by heightened inflammation or intestinal permeability reported poorer focus and marginally poorer memory. However, poorer performance across objective cognitive measures was not specific to inflammation-associated depression. Rather, there was some evidence of lower verbal fluency; poorer attention, verbal learning and memory, and working memory; and difficulties with visuospatial search among depressed survivors, regardless of inflammation. By themselves, inflammation and intestinal permeability less consistently predicted subjective or objective cognitive function. Breast cancer survivors with clinically significant depressive symptoms accompanied by either elevated inflammation or intestinal permeability may perceive greater cognitive difficulty, even though depression-related objective cognitive deficits may not be specific to inflammation- or leaky-gut-associated depression. [ABSTRACT FROM AUTHOR]

Background Declines in the prevalence of cigarette smoking, advances in targeted therapies, and implementation of lung cancer screening have changed the clinical landscape for lung cancer. The proportion of lung cancer deaths is increasing in those who have never smoked cigarettes. To better understand contemporary patterns in survival among patients with lung cancer, a comprehensive evaluation of factors associated with survival, including differential associations by smoking status, is needed. Methods Patients diagnosed with lung cancer between January 1, 2010, and September 30, 2019, were identified. We estimated all-cause and lung cancer-specific median, 5-year, and multivariable restricted mean survival time (RMST) to identify demographic, socioeconomic, and clinical factors associated with survival, overall and stratified by smoking status (never, former, and current). Results Analyses included 6813 patients with lung cancer: 13.9% never smoked, 54.2% formerly smoked, and 31.9% currently smoked. All-cause RMST through 5 years for those who never, formerly, and currently smoked was 32.1, 25.9, and 23.3 months, respectively. Lung cancer–specific RMST was 36.3 months, 30.3 months, and 26.0 months, respectively. Across most models, female sex, younger age, higher socioeconomic measures, first-course surgery, histology, and body mass index were positively associated, and higher stage was inversely associated with survival. Relative to White patients, Black patients had increased survival among those who formerly smoked. Conclusions We identify actionable factors associated with survival between those who never, formerly, and currently smoked cigarettes. These findings illuminate opportunities to address underlying mechanisms driving lung cancer progression, including use of first-course treatment, and enhanced implementation of tailored smoking cessation interventions for individuals diagnosed with cancer. [ABSTRACT FROM AUTHOR]

Purpose: Determining the frequency and distribution of pathogenic germline variants (PGVs) in Austrian prostate cancer (PCa) patients and to assess the accuracy of different clinical risk scores to correctly predict PGVs. Methods: This cross-sectional study included 313 men with advanced PCa. A comprehensive personal and family history was obtained based on predefined questionnaires. Germline DNA sequencing was performed between 2019 and 2021 irrespective of family history, metastatic or castration status or age at diagnosis. Clinical risk scores for hereditary cancer syndromes were evaluated and a PCa-specific score was developed to assess the presence of PGVs. Results: PGV presence was associated with metastasis (p = 0.047) and castration resistance (p = 0.011), but not with personal cancer history or with relatives with any type of cancer. Clinical risk scores (Manchester score, PREMM5 score, Amsterdam II criteria or Johns Hopkins criteria) showed low sensitivities (3.3–20%) for assessing the probability of PGV presence. A score specifically designed for PCa patients stratifying patients into low- or high-risk regarding PGV probability, correctly classified all PGV carriers as high-risk, whereas a third of PCa patients without PGVs was classified as low risk of the presence of PGVs. Conclusion: Application of common clinical risk scores based on family history are not suitable to identify PCa patients with high PGV probabilities. A PCa-specific score stratified PCa patients into low- or high-risk of PGV presence with sufficient accuracy, and germline DNA sequencing may be omitted in patients with a low score. Further studies are needed to evaluate the score. [ABSTRACT FROM AUTHOR]

Simple Summary: Rates of early-onset colorectal cancer (eoCRC), defined as <50 years of age at diagnosis, have increased. Nearly one-quarter of cases of eoCRC may be associated with a germline pathogenic variant (PGV) resulting in a hereditary cancer syndrome. In the present study, we reviewed patients with a history of colorectal cancer who were referred to medical genetics at our institution to better understand the prevalence and spectrum of PGVs in both patients with eoCRC as well as with average-onset CRC (aoCRC). We found that approximately one in four patients with eoCRC had a PGV, which included 8.3% with Lynch syndrome. In patients with aoCRC, similar rates of detection of PGVs were seen. In both groups, approximately one-third of patients referred to medical genetics did not undergo genetic testing. This study reinforces the importance for patients with CRC to undergo genetic testing, especially those with eoCRC. Over the past 20 years, rates of early-onset colorectal cancer (eoCRC), defined as <50 years of age at diagnosis, have increased, with 16–25% associated with a pathogenic germline variant (PGV) resulting in a hereditary cancer syndrome. In the present study, we sought to further characterize PGVs observed in patients with eoCRC. We conducted a retrospective analysis of patients with a history of CRC referred for genetic counseling at Mayo Clinic Rochester between April 2019 and April 2022. Three hundred and three CRC patients were referred to medical genetics, including 124 with a history of eoCRC. Only 84 patients (68%) with eoCRC referred for genetic counseling completed genetic testing, with an average of 48 genes evaluated. PGVs were identified in 27.4% with eoCRC, including 8.3% with Lynch syndrome (LS). Other detected PGVs known to increase the risk of CRC included MUTYH (4.8%), CHEK2 (3.6%), APC, BMPR1A, and TP53 (1.3% each). Among those with aoCRC, 109 patients (61%) completed genetic testing, among which 88% had either a dMMR tumor, personal history of an additional LS malignancy, or family history of LS malignancy, with PGVs detected in 23% of patients. This study reinforces the importance for all patients with CRC, especially those with eoCRC, to undergo germline testing. [ABSTRACT FROM AUTHOR]

Extrachromosomal DNA (ecDNA) is circular DNA that plays an important role in the development and heterogeneity of cancer. The rapid evolution of methods to detect ecDNA, including microscopic and sequencing approaches, has greatly enhanced our knowledge of the role of ecDNA in cancer development and evolution. Here, we review the molecular characteristics, functions, mechanisms of formation, and detection methods of ecDNA, with a focus on the potential clinical implications of ecDNA in cancer. Specifically, we consider the role of ecDNA in acquired drug resistance, as a diagnostic and prognostic biomarker, and as a therapeutic target in the context of cancer. As the pathological and clinical significance of ecDNA continues to be explored, it is anticipated that ecDNA will have broad applications in the diagnosis, prognosis, and treatment of patients with cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Treatment-related symptoms such as fatigue, depression, and disruptions in sleep and physical activity are common and distressing in gynecologic cancer patients. The aim of our study was to examine whether higher levels of inflammation are associated with worse symptomatology, and if these associations are stronger for patients with gynecologic cancer (n = 121) than age-matched women without a cancer history (i.e., controls; n = 105). Elevated levels of C-reactive protein were associated with depression and disrupted physical activity, but there were no other significant associations between inflammation and treatment-related symptoms. Findings suggest that inflammation may not play a significant role in the development of fatigue or sleep disturbance among gynecologic cancer patients but may contribute to depression and physical inactivity. Previous research suggests that inflammation triggers cancer-treatment-related symptoms (i.e., fatigue, depression, and disruptions in sleep and physical activity), but evidence is mixed. This study examined relationships between inflammatory biomarkers and symptoms in patients with gynecologic cancer compared to age-matched women with no cancer history (i.e., controls). Patients (n = 121) completed assessments before chemotherapy cycles 1, 3, and 6, and 6 and 12 months later. Controls (n = 105) completed assessments at similar timepoints. Changes in inflammation and symptomatology were evaluated using random-effects mixed models, and cross-sectional differences between patients and controls in inflammatory biomarkers and symptoms were evaluated using least squares means. Associations among inflammatory biomarkers and symptoms were evaluated using random-effects fluctuation mixed models. The results indicated that compared to controls, patients typically have higher inflammatory biomarkers (i.e., TNF-alpha, TNFR1, TNFR2, CRP, IL-1ra) and worse fatigue, depression, and sleep (ps < 0.05). Patients reported lower levels of baseline physical activity (p = 0.02) that became more similar to controls over time. Significant associations were observed between CRP, depression, and physical activity (ps < 0.05), but not between inflammation and other symptoms. The results suggest that inflammation may not play a significant role in fatigue or sleep disturbance among gynecologic cancer patients but may contribute to depression and physical inactivity. [ABSTRACT FROM AUTHOR]

Simple Summary: The current study investigated the potential use of fluorometric cfDNA quantification as a prognostic biomarker in advanced non-small cell lung cancer (NSCLC) patients treated with an Immune Checkpoint Blockade (ICB). Results showed that a cfDNA cut-off of 0.55 ng/µL before the ICB determines the overall survival of patients with a log rank p-value of 3.3 × 10−4. High cfDNA concentrations identify patients with advanced NSCLC who do not benefit from ICB. The determination of cfDNA is a simple test that could select a group of patients in whom new therapeutic strategies are needed. The present study aimed to investigate the potential of basal cell-free fluorometric DNA (cfDNA) quantification as a prognostic biomarker in advanced non-small cell lung cancer (NSCLC) patients treated with an Immune Checkpoint Blockade (ICB). A discovery and validation cohort of 61 and 31 advanced lung cancer patients treated with ICB were included in this study. Quantification of cfDNA concentration was performed before the start of the treatment and patients were followed up for a median of 34 (30–40) months. The prognostic predicted value of cfDNA was evaluated based on ROC, and Cox regression was conducted via univariate and multivariate analyses to estimate the hazard ratio. We observed that a cfDNA cut-off of 0.55 ng/µL before the ICB determines the overall survival of patients with a log rank p-value of 3.3 × 10−4. That represents median survivals of 3.8 vs. 17.5 months. Similar results were obtained in the validation cohort being the log rank p-value 3.8 × 10−2 with median survivals of 5.9 vs. 24.3. The univariate and multivariate analysis revealed that the cut-off of 0.55 ng/µL before ICB treatment was an independent predictive factor and was significantly associated with a better survival outcome. High cfDNA concentrations identify patients with advanced NSCLC who do not benefit from the ICB. The determination of cfDNA is a simple test that could select a group of patients in whom new therapeutic strategies are needed. [ABSTRACT FROM AUTHOR]

Key Points: Question: Among patients with cancer and a venous thromboembolism (VTE) event, are direct oral anticoagulants noninferior to low-molecular-weight heparin for preventing recurrent VTE events? Findings: In this pragmatic, noninferiority randomized clinical trial that included 638 patients from 67 centers with cancer and a new VTE, direct oral anticoagulants, compared with low-molecular-weight heparin, resulted in a recurrent VTE rate of 6.1% vs 8.8% at 6 months. The upper confidence limit around the difference was less than the noninferiority margin of 3%. Meaning: Among adults with cancer and VTE, direct oral anticoagulants were noninferior to low-molecular-weight heparin for preventing recurrent VTE over 6-month follow-up. Importance: In patients with cancer who have venous thromboembolism (VTE) events, long-term anticoagulation with low-molecular-weight heparin (LMWH) is recommended to prevent recurrent VTE. The effectiveness of a direct oral anticoagulant (DOAC) compared with LMWH for preventing recurrent VTE in patients with cancer is uncertain. Objective: To evaluate DOACs, compared with LMWH, for preventing recurrent VTE and for rates of bleeding in patients with cancer following an initial VTE event. Design, Setting, and Participants: Unblinded, comparative effectiveness, noninferiority randomized clinical trial conducted at 67 oncology practices in the US that enrolled 671 patients with cancer (any invasive solid tumor, lymphoma, multiple myeloma, or chronic lymphocytic leukemia) who had a new clinical or radiological diagnosis of VTE. Enrollment occurred from December 2016 to April 2020. Final follow-up was in November 2020. Intervention: Participants were randomized in a 1:1 ratio to either a DOAC (n = 335) or LMWH (n = 336) and were followed up for 6 months or until death. Physicians and patients selected any DOAC or any LMWH (or fondaparinux) and physicians selected drug doses. Main Outcomes and Measures: The primary outcome was the recurrent VTE rate at 6 months. Noninferiority of anticoagulation with a DOAC vs LMWH was defined by the upper limit of the 1-sided 95% CI for the difference of a DOAC relative to LMWH of less than 3% in the randomized cohort that received at least 1 dose of assigned treatment. The 6 prespecified secondary outcomes included major bleeding, which was assessed using a 2.5% noninferiority margin. Results: Between December 2016 and April 2020, 671 participants were randomized and 638 (95%) completed the trial (median age, 64 years; 353 women [55%]). Among those randomized to a DOAC, 330 received at least 1 dose. Among those randomized to LMWH, 308 received at least 1 dose. Rates of recurrent VTE were 6.1% in the DOAC group and 8.8% in the LMWH group (difference, −2.7%; 1-sided 95% CI, −100% to 0.7%) consistent with the prespecified noninferiority criterion. Of 6 prespecified secondary outcomes, none were statistically significant. Major bleeding occurred in 5.2% of participants in the DOAC group and 5.6% in the LMWH group (difference, −0.4%; 1-sided 95% CI, –100% to 2.5%) and did not meet the noninferiority criterion. Severe adverse events occurred in 33.8% of participants in the DOAC group and 35.1% in the LMWH group. The most common serious adverse events were anemia and death. Conclusions and Relevance: Among adults with cancer and VTE, DOACs were noninferior to LMWH for preventing recurrent VTE over 6-month follow-up. These findings support use of a DOAC to prevent recurrent VTE in patients with cancer. Trial Registration: ClinicalTrials.gov Identifier: NCT02744092 This randomized trial assesses the comparative effectiveness of direct oral anticoagulants vs low-molecular-weight heparin on rate of 6-month recurrence of venous thromboembolism (VTE) among patients with cancer who had a new diagnosis of VTE. [ABSTRACT FROM AUTHOR]

Purpose: The current study summarized the clinical course and treatment outcomes of intestinal cancer in CD seen in our department and explored the steps to take in the future. Methods: Subjects were patients who had been diagnosed with CD at our hospital and who underwent surgery in our department from 1985 to 2020. Results: Thirty-one patients had CD and intestinal cancer, including 6 with cancer of the small intestine and 25 with cancer of the large intestine. In all six patients with cancer of the small intestine, the site where cancer or a tumor developed was at or near the site of the anastomosis made at a previous surgery. Of the 25 patients with cancer of the large intestine, 22 developed cancer in the rectum or anal region. Conclusion: Many of the patients with cancer of the small intestine had previously undergone surgery, and the cancer developed at or near the site of the anastomosis. In patients who have previously undergone resection of the small intestine, the small intestine needs to be examined regularly. Cancer of the large intestine often developed in the rectum or anal region of our patients, so a detailed examination of the same site needs to be performed. [ABSTRACT FROM AUTHOR]

Simple Summary: Although the tumor cell-intrinsic cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway plays a crucial role in activating immune cells in the tumor microenvironment in colorectal cancer (CRC), its impact on the infiltration of immune cells and clinical outcomes in patients with mismatch repair proficient/microsatellite stable (pMMR/MSS) CRC has not been thoroughly investigated. In this study, we examine the expression pattern of cGAS-STING in tumor cells and its effect on the infiltrations of CD8+ and CD4+ T cells, as well as clinical outcomes including survival and recurrence in patients with pMMR/MSS CRC. Our current findings may offer novel insights and therapeutic strategies for patients with pMMR/MSS CRC. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway plays a crucial role in activating immune cells in the tumor microenvironment, thereby contributing to a more favorable response to immune checkpoint inhibitors (ICI) in colorectal cancer (CRC). However, the impact of the expression of cGAS-STING in tumor cells on the infiltration of CD8+ T cells and clinical outcomes in mismatch repair proficient/microsatellite stable (pMMR/MSS) CRC remains largely unknown. Our findings reveal that 56.8% of all pMMR CRC cases were cGAS-negative/STING-negative expressions (cGAS−/STING−) in tumor cells, whereas only 9.9% of all pMMR CRC showed cGAS-positive/STING-positive expression (cGAS+/STING+) in tumor cells. The frequency of cGAS+/STING+ cases was reduced in the advanced stages of pMMR/MSS CRC, and histone methylation might be involved in the down-regulation of STING expression in tumor cells. Since the expression level of cGAS-STING in tumor cells has been associated with the infiltration of CD8+ and/or CD4+ T cells and the frequency of recurrence in pMMR/MSS CRC, decreased expression of cGAS-STING in tumor cells might lead to poor immune cell infiltration and worse prognosis in most pMMR/MSS CRC patients. Our current findings provide a novel insight for the treatment of patients with pMMR/MSS CRC. [ABSTRACT FROM AUTHOR]

Purpose: The current study aimed to explore the prognosis of ovarian cancer patients in different subgroup using three prognostic research indexes. The current study aimed to build a prognostic model for ovarian cancer patients. Methods: The study dataset was downloaded from Surveillance Epidemiology and End Results database. Accelerated Failure Time algorithm was used to construct a prognostic model for ovary cancer. Results: The mortality rate in the model group was 51.6% (9,314/18,056), while the mortality rate in the validation group was 52.1% (6,358/12,199). The current study constructed a prognostic model for ovarian cancer patients. The C indexes were 0.741 (95% confidence interval: 0.731–0.751) in model dataset and 0.738 (95% confidence interval: 0.726–0.750) in validation dataset. Brier score was 0.179 for model dataset and validation dataset. The C indexes were 0.741 (95% confidence interval: 0.733–0.749) in bootstrap internal validation dataset. Brier score was 0.178 for bootstrap internal validation dataset. Conclusion: The current research indicated that there were significant differences in the survival benefits of treatments among ovarian cancer patients with different stages. The current research developed an individual mortality risk predictive system that could provide valuable predictive information for ovarian cancer patients. [ABSTRACT FROM AUTHOR]

Checkpoint inhibitors can be a highly effective antitumor therapy but only to a subset of patients, presumably due to immunotherapy resistance. Fluoxetine was recently revealed to inhibit the NLRP3 inflammasome, and NLRP3 inhibition could serve as a target for immunotherapy resistance. Therefore, we evaluated the overall survival (OS) in patients with cancer receiving checkpoint inhibitors combined with fluoxetine. A cohort study was conducted among patients diagnosed with lung, throat (pharynx or larynx), skin, or kidney/urinary cancer treated with checkpoint inhibitor therapy. Utilizing the Veterans Affairs Informatics and Computing Infrastructure, patients were retrospectively evaluated during the period from October 2015 to June 2021. The primary outcome was overall survival (OS). Patients were followed until death or the end of the study period. There were 2316 patients evaluated, including 34 patients who were exposed to checkpoint inhibitors and fluoxetine. Propensity score weighted Cox proportional hazards demonstrated a better OS in fluoxetine-exposed patients than unexposed (HR: 0.59, 95% CI 0.371–0.936). This cohort study among cancer patients treated with checkpoint inhibitor therapy showed a significant improvement in the OS when fluoxetine was used. Because of this study's potential for selection bias, randomized trials are needed to assess the efficacy of the association of fluoxetine or another anti-NLRP3 drug to checkpoint inhibitor therapy. [ABSTRACT FROM AUTHOR]

Purpose: High-quality population-based cancer recurrence data are scarcely available, mainly due to complexity and cost of registration. For the first time in Belgium, we developed a tool to estimate distant recurrence after a breast cancer diagnosis at the population level, based on real-world cancer registration and administrative data. Methods: Data on distant cancer recurrence (including progression) from patients diagnosed with breast cancer between 2009– 2014 were collected from medical files at 9 Belgian centers to train, test and externally validate an algorithm (i.e., gold standard). Distant recurrence was defined as the occurrence of distant metastases between 120 days and within 10 years after the primary diagnosis, with follow-up until December 31, 2018. Data from the gold standard were linked to population-based data from the Belgian Cancer Registry (BCR) and administrative data sources. Potential features to detect recurrences in administrative data were defined based on expert opinion from breast oncologists, and subsequently selected using bootstrap aggregation. Based on the selected features, classification and regression tree (CART) analysis was performed to construct an algorithm for classifying patients as having a distant recurrence or not. Results: A total of 2507 patients were included of whom 216 had a distant recurrence in the clinical data set. The performance of the algorithm showed sensitivity of 79.5% (95% CI 68.8– 87.8%), positive predictive value (PPV) of 79.5% (95% CI 68.8– 87.8%), and accuracy of 96.7% (95% CI 95.4– 97.7%). The external validation resulted in a sensitivity of 84.1% (95% CI 74.4– 91.3%), PPV of 84.1% (95% CI 74.4– 91.3%), and an accuracy of 96.8% (95% CI 95.4– 97.9%). Conclusion: Our algorithm detected distant breast cancer recurrences with an overall good accuracy of 96.8% for patients with breast cancer, as observed in the first multi-centric external validation exercise. [ABSTRACT FROM AUTHOR]

To assess the potential clinical utility of cell-free DNA (cfDNA)-based biomarkers for identifying gastric cancer (GC) patients who benefit from nivolumab. From 31 GC patients treated with nivolumab monotherapy (240 mg/body, Bi-weekly) in 3rd or later line setting, we prospectively collected blood samples at baseline and before the 3rd dose. We compared cfDNA-based molecular findings, including microsatellite instability (MSI) status, to tissue-based biomarkers. We assessed the clinical value of blood tumor mutation burden (bTMB) and copy number alterations (CNA) as well as the cfDNA dynamics. The concordance between deficient-MMR and cfDNA-based MSI-high was 100% (3/3). Patients with bTMB ≥ 6 mut/Mb had significantly better progression-free survival (PFS) and overall survival (OS); however, such significance disappeared when excluding MSI-High cases. The combination of bTMB and CNA positivity identified patients with survival benefit regardless of MSI status (both PFS and OS, P < 0.001), with the best survival in those with bTMB≥6mut/Mb and CNAnegative. Moreover, patients with decreased bTMB during treatment had a better disease control rate (P = 0.04) and longer PFS (P = 0.04). Our results suggest that a combination of bTMB and CNA may predict nivolumab efficacy for GC patients regardless of MSI status. bTMB dynamics have a potential utility as an on-treatment biomarker. [ABSTRACT FROM AUTHOR]

Colorectal cancer is one of the most frequently occurring cancers today, with a large percentage of cases having a hereditary basis. Lynch syndrome is the most common cause of hereditary colorectal cancer. The genetic defect characteristics of this syndrome involve mutations in mismatch repair (MMR) genes, which result in microsatellite instability. Early detection of the mutation can help evaluate the cancer risk and, consequently, a proper course of clinical management for the person harboring the mutation. Herein, we describe the first report of a c.1458dup (p.Glu487*) new mutation in a 53-year-old colorectal cancer patient with diagnosed Lynch syndrome. Additionally, the existence of lipomas in this patient and his family could be related to this syndrome. Further investigation may provide a possible visual clue that can indicate a need for genetic screening. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer-related fatigue (CRF) is a common somatic discomfort in gynecological cancer patients; however, it is usually overlooked by physicians. We aimed to explore the prevalence of CRF's and the clinical characteristics of gynecological cancer patients. The results showed that 77.9% of patients had received related CRF management. A five-item predictive model was developed from the identified risk factors contributing to CRF. The risk factors included (1) diagnosis of endometrial/cervical cancer, (2) International Federation of Gynecology and Obstetrics (FIGO) stage >1, (3) Eastern Cooperative Oncology Group (ECOG) status score ≥1, (4) inadequate treatment response, and (5) having received cancer treatment in the past 1 week. The predictive model may help physicians more promptly identify high-risk patients in clinical practice. Cancer-related fatigue (CRF) is the most common somatic discomfort in patients with gynecological cancers. CRF is often overlooked; however, it can impair the patients' quality of life considerably. This cross-sectional study aimed to identify the clinical characteristics of CRF in gynecological cancer patients. Questionnaires and the International Classification of Diseases 10th Revision (ICD-10) criteria were used to identify CRF. The enrolled patients were further categorized according to the amount of fatigue-related management received. Of the enrolled 190 patients, 40.0% had endometrial cancer, 28.9% had cervical cancer, and 31.1% had ovarian cancer. On the basis of the ICD-10 diagnostic criteria, 42.6% had non-cancer-related fatigue, 10% had CRF, and 51% had BFI-T questionnaire-based fatigue. Moreover, 77.9% of the study cohort had ever received fatigue-related management. Further analysis showed that patients with endometrial/cervical cancer, International Federation of Gynecology and Obstetrics stage >1, Eastern Cooperative Oncology Group performance status score ≥1, inadequate cancer treatment response, and receiving cancer treatment in the past week had a higher probability of receiving more fatigue-related management. The five-item predictive model developed from these factors may help physicians recognize patients seeking more fatigue-related management more efficiently. This is important as they may suffer from a more profound CRF. [ABSTRACT FROM AUTHOR]

Purpose: Little is known about the prognostic factors for survival after endoscopic submucosal dissection (ESD) in elderly patients with early gastric cancer (EGC). The aim of this study is to determine prognostic factors and a prediction model of 3-year survival after ESD for EGC in patients aged ≥ 85 years. Methods: We retrospectively evaluated the clinical outcomes of 740 patients with EGC aged ≥ 85 years, who were treated by ESD at 30 institutions in Japan. Overall survival (OS) and disease-specific survival (DSS) were calculated with the Kaplan–Meier method. Prediction models for 3-year OS after ESD were estimated using the Cox proportional hazards model based on Uno's C-statistics. Results: During the follow-up period, 309 patients died of any cause and 10 patients died of gastric cancer. OS and DSS after 3 years were 82.7% and 99.2%, respectively. No significant differences in OS were found among curability categories. The Cox proportional hazards model revealed the geriatric nutritional risk index (GNRI) and the Charlson comorbidity index (CCI) to be predictors of 3-year survival. We established a final model (EGC-2 model) expressed by GNRI − (2.2×CCI) with a cutoff value of 96. The overall survival rate was significantly lower in the model value < 96 group than in the model value ≥ 96 group (P < 0.001). Conclusions: The prediction model using GNRI and CCI will be useful to support decision-making for the treatment of EGC in elderly patients aged ≥ 85 years. [ABSTRACT FROM AUTHOR]

Background: A growing number of lifestyle interventions are being developed to promote weight loss and adoption of a healthful lifestyles among breast cancer survivors; yet Black and Latina women remain underrepresented. Purpose: We performed a scoping review of the available peer-reviewed literature to describe and compare the content, design, methods, and primary outcomes of current diet and/or physical activity (PA) interventions after a breast cancer diagnosis among Black and Latina women. Methods: We queried PubMed, EMBASE, CINAHL, MEDLINE, and Clinicaltrials.gov up to October 1, 2022, to identify all randomized controlled trials of diet and/or PA after diagnosis of breast cancer with a majority (>50%) of Black or Latina participants. Results: Twenty-two randomized controlled trials were included in this review (five efficacy, twelve pilot, five on-going). Nine trials were among Latinas (two diet, four PA, and three diet/PA), six among Blacks (one PA and five diet/PA) and seven included both populations (five PA and two diet/PA), all of which examined different endpoints. Two of the five efficacy studies achieved their a priori outcome (one diet trial improved short term dietary intake; one PA trial achieved clinically significant improvements in metabolic syndrome score), both in Latinas. Eight pilot trials intervened on both diet and PA and three of them found favorable behavioral changes. Three (two for Latinas and one for Blacks) out of the nine diet and PA trials and three (all for Latinas) efficacy trials incorporated a culturally focused approach (i.e., traditional foods, music, Spanish content, bicultural health coaches, spirituality). Overall, four trials, including one efficacy trial, had one-year follow-up data, with three finding sustained behavior change. Electronic/mobile components were incorporated in five trials and one involved informal care givers. Most of the trials were geographically limited to the Northeast USA (n=8, NY, NC, DC, NJ) and Texas (n=4). Conclusions: Most of the trials we identified were pilot or feasibility studies and of short duration, demonstrating the need for large randomized controlled efficacy lifestyle interventions among Black and Latina breast cancer survivors. Culturally tailored programing was limited but is an important component to incorporate in future trials in these populations. [ABSTRACT FROM AUTHOR]

Simple Summary: Goals-of-care discussions can help patients to understand their illness and to share their values and treatment preferences with their clinicians. Here, we compared the impact of an institution-wide goals-of-care program on intensive care unit (ICU) mortality between patients with hematologic malignancies and solid tumors. We found that patients with blood cancers had improved goals-of-care documentation, but no change in ICU mortality; in contrast, patients with solid tumors had lesser improvement in goals-of-care documentation, but significantly lower ICU mortality. These findings highlight the need to overcome other barriers to improve care for patients with hematologic malignancies. We recently reported that an interdisciplinary multicomponent goals-of-care (myGOC) program was associated with an improvement in goals-of-care (GOC) documentation and hospital outcomes; however, it is unclear if the benefit was uniform between patients with hematologic malignancies and solid tumors. In this retrospective cohort study, we compared the change in hospital outcomes and GOC documentation before and after myGOC program implementation between patients with hematologic malignancies and solid tumors. We examined the change in outcomes in consecutive medical inpatients before (May 2019–December 2019) and after (May 2020–December 2020) implementation of the myGOC program. The primary outcome was intensive care unit (ICU) mortality. Secondary outcomes included GOC documentation. In total, 5036 (43.4%) patients with hematologic malignancies and 6563 (56.6%) with solid tumors were included. Patients with hematologic malignancies had no significant change in ICU mortality between 2019 and 2020 (26.4% vs. 28.3%), while patients with solid tumors had a significant reduction (32.6% vs. 18.8%) with a significant between-group difference (OR 2.29, 95% CI 1.35, 3.88; p = 0.004). GOC documentation improved significantly in both groups, with greater changes observed in the hematologic group. Despite greater GOC documentation in the hematologic group, ICU mortality only improved in patients with solid tumors. [ABSTRACT FROM AUTHOR]

Simple Summary: The risk factors for symptomatic spinal metastasis (SSM) onset remain unclear. This prospective cohort study aimed to statistically analyze the significant risk factors. One hundred and twenty-eight asymptomatic patients were prospectively registered. Data were collected from sixteen candidates regarding independent demographic and clinical factors, including Spinal Neoplastic Instability Score (SINS). Multivariate analysis was performed to identify the risk factors for SSM onset. Furthermore, the threshold was calculated from the receiver operating characteristic curve using the Youden index. Thirty-seven patients (28.9%) developed SSM during the follow-up period. The total SINS was identified as the most significant factor. The cut-off value for the SINS was 9.5 (sensitivity: 67.6%; specificity: 83.5%). This study identified the significant risk factors for SSM onset and the threshold of the SINS. If long-term survival is expected, patients with a SINS ≥ 10 should be considered for intervention to prevent SSM. Background: Symptomatic spinal metastasis (SSM) decreases the activities of daily living (ADL) and quality of life of cancer patients. However, the risk factors for SSM onset remain unclear. This prospective cohort study aimed to statistically analyze the significant risk factors. Methods: From 2016 to 2018, 210 consecutive patients with spinal metastases were prospectively registered. Patients with SSM at the first consultation and those who were unable to be followed-up owing to poor general condition were excluded. The demographic factors (age, sex, primary cancer, performance status, and ADL), clinical factors (radiation therapy, chemotherapy, molecularly targeted drugs, and bone-modifying agents (BMAs)), and Spinal Neoplastic Instability Score (SINS) were evaluated. Multivariate analysis was performed to identify the risk factors for SSM onset. Furthermore, the threshold was calculated from the receiver operating characteristic curve using the Youden index. Results: Thirty-nine patients who presented with SSM at the first consultation and 43 patients who were unable to be followed-up owing to poor general condition were excluded. Finally, 128 asymptomatic patients were included. Thirty-seven patients (28.9%) developed SSM during the follow-up period. The total SINS (OR: 1.739; 95% CI: 1.345–2.250) was identified as the most significant factor. The cut-off value of the SINS was 9.5 (sensitivity: 67.6%; specificity: 83.5%). Twenty-five (62.5%) of the forty patients with a SINS ≥ 10 developed SSM within a mean of 5.5 months (95% CI: 1.17–9.83). Furthermore, all patients with a SINS ≥ 13 developed SSM (n = 5) within a mean of 1.37 months (95% CI: 0.0–3.01). Conclusions: This study identified the significant risk factors for SSM onset and the threshold of the SINS. If long-term survival is expected, patients with a SINS ≥ 10 should be considered for intervention to prevent SSM. [ABSTRACT FROM AUTHOR]

Simple Summary: The major histocompatibility complex (MHC) class I genes, encompassing the human leukocyte antigen (HLA) class I and the beta-2 microglobulin (B2M) genes, play a key role in neoantigens presentation to the immune system. We analyzed allelic imbalance (AI) of the respective chromosomal regions by multiplex PCRs using microsatellite markers in biopsies of 158 patients with gastric/gastroesophageal adenocarcinoma before neoadjuvant platinum/fluoropyrimidine chemotherapy (CTx) for an association with clinical outcome of the patients. AI with no marker was significantly associated with response or survival. However, subgroup analysis revealed interesting differences. Of note, AI at markers of the HLA region was associated with a decreased survival only in responding but not in non-responding patients. No associations were observed for B2M markers. Our results underline the importance of intact neoantigen presentation specifically for responding patients and may help explain an unexpectedly poor survival of a patient despite significant tumor regression after neoadjuvant CTx. We aimed to determine the clinical and prognostic relevance of allelic imbalance (AI) of the major histocompatibility complex (MHC) class I genes, encompassing the human leukocyte antigen (HLA) class I and beta-2 microglobulin (B2M) genes, in the context of neoadjuvant platinum/fluoropyrimidine chemotherapy (CTx). Biopsies before CTx were studied in 158 patients with adenocarcinoma of the stomach or gastroesophageal junction. The response was histopathologically evaluated. AI was detected by multiplex PCRs analysis of four or five microsatellite markers in HLA and B2M regions, respectively. AI with no marker was significantly associated with response or survival. However, subgroup analysis revealed differences. AI at marker D6S265, close to the HLA-A gene, was associated with an obvious increased risk in responding (HR, 3.62; 95% CI, 0.96–13.68, p = 0.058) but not in non-responding patients (HR, 0.92; 95% CI, 0.51–1.65, p = 0.773). Markers D6S273 and D6S2872 showed similar results. The interaction between AI at D6S265 and response to CTx was significant in a multivariable analysis (p = 0.010). No associations were observed for B2M markers. Our results underline the importance of intact neoantigen presentation specifically for responding patients and may help explain an unexpectedly poor survival of a patient despite significant tumor regression after neoadjuvant platinum/fluoropyrimidine CTx. [ABSTRACT FROM AUTHOR]

Background: Accurate prognostic prediction of survival in cervical cancer patients with bone metastasis is important for treatment planning. We aimed to externally validate the Matsumiya scoring system using external patient data. Methods: We collected a retrospective cohort of patients with cervical cancer diagnosed with bone metastasis at Chiang Mai University Hospital from 1st January 2007 to 31st December 2016. The Matsumiya score was composed of 5 predictors, including the presence of extraskeletal metastasis, ECOG performance status, history of previous chemo- or radiotherapy, the presence of multiple bone metastasis, and bone metastasis-free interval < 12 months. Harrell's C-statistics and score calibration plots were used to evaluate the score performance. We also reconstructed the development study to estimate apparent performance values for comparison during external validation. Results: A total of 124 cervical cancer patients with bone metastasis were included in this study. The 13-, 26-, and 52-week survival probabilities in the validation study were 70.1%, 50.5%, and 25.7%, respectively. Several differences were identified between development and validation studies regarding clinical characteristics, case-mix, and predictor–outcome associations. Harrell's C-statistics in the development and validation study were 0.714 and 0.567. The score showed poor agreement between the observed and the predicted survival probabilities in the validation study. Score reweighting and refitting showed only modest improvement in performance. Conclusion: A prognostic scoring system by Matsumiya et al. performed poorly in our cohort of Thai cervical cancer patients with bone metastasis. We suggested that the score should be sufficiently updated before being used. [ABSTRACT FROM AUTHOR]

Predicting when a patient with advanced cancer is dying is a challenge and currently no prognostic test is available. We hypothesised that a dying process from cancer is associated with metabolic changes and specifically with changes in volatile organic compounds (VOCs). We analysed urine from patients with lung cancer in the last weeks of life by headspace gas chromatography mass spectrometry. Urine was acidified or alkalinised before analysis. VOC changes in the last weeks of life were identified using univariate, multivariate and linear regression analysis; 12 VOCs increased (11 from the acid dataset, 2 from the alkali dataset) and 25 VOCs decreased (23 from the acid dataset and 3 from the alkali dataset). A Cox Lasso prediction model using 8 VOCs predicted dying with an AUC of 0.77, 0.78 and 0.85 at 30, 20 and 10 days and stratified patients into a low (median 10 days), medium (median 50 days) or high risk of survival. Our data supports the hypothesis there are specific metabolic changes associated with the dying. The VOCs identified are potential biomarkers of dying in lung cancer and could be used as a tool to provide additional prognostic information to inform expert clinician judgement and subsequent decision making. [ABSTRACT FROM AUTHOR]

Germline genetic testing is recommended for all patients with pancreatic cancer (PC) but uptake rates are low. We implemented a mainstreaming program in oncology clinics to increase testing for PC patients. Genetic counselors trained oncology providers to offer a standardized multigene panel and obtain informed consent using an educational video. Pre-test genetic counseling was available upon request. Otherwise, patients with identified pathogenic variants, strong family history, or questions regarding their results were referred for post-test genetic counseling. We measured rates of testing and genetic counseling visits. From September 2019 to April 2021, 245 patients with PC underwent genetic testing. This represents a 6.5-fold increase in germline testing volume (95% confidence interval 5.2–8.1) compared to previous years. At least one pathogenic or likely pathogenic variant (PV/LPV) was found in 34 (13.9%) patients, including 17 (6.9%) PV/LPVs in high or moderate risk genes and 18 (7.3%) in low risk or recessive genes. Five (2.0%) PVs had implications on treatment selection. 22 of the positive patients (64.7%) and an additional 8 PC patients (1 negative, 3 VUS, and 4 pre-test) underwent genetic counseling during the study period. Genetic counselors saw 2.0 PC patients/month prior to this project, 1.6 PC patients/month during this project, and would have seen 2.2 PC patients/month if all patients with pathogenic variants attended post-test counseling. Conclusions Mainstreaming genetic testing expands access for PC patients without overwhelming genetic counseling resources. [ABSTRACT FROM AUTHOR]

Background: Assessment of illness and treatment understanding among cancer patients has largely focused on those with advanced disease. Less is known about patient expectations at earlier stages of cancer and potential modifiers of accurate understanding. Methods: We assessed accuracy of cure expectations in patients across all stages with gastrointestinal (GI) cancers. Accuracy was determined by independent reviews of patient health records by oncologists on the investigative team. Impact on cure accuracy of selected clinical variables and health‐information preferences was analyzed. Results: Hundred and thirty five patients were included for analysis, with 100% interrater agreement for accuracy between oncologist reviewers. Sixety five patients (48%) had accurate cure expectations from their cancer treatment. Accuracy was lower in Stage IV versus Stage I–III disease (35% vs. 63%, p < 0.01), lower in unresectable versus resectable disease (35% vs. 67%, p < 0.01), and higher in patients with early‐stage disease who received adjuvant chemotherapy versus those who did not (78% vs. 53%, p = 0.04). Accuracy did not differ by health‐information preferences and remained stable over time. Of 63 patients who died, baseline accuracy differed by location of death (p = 0.03), with greater accuracy in those who died with home hospice (56%). Accuracy was lower in those who were hospitalized in the last 30 days of life versus those who were not (25% vs. 59%, p = 0.01). Conclusions: Inaccurate cure expectations are prevalent across all stages of GI cancers, but particularly among those with metastatic or unresectable disease. High‐quality, iterative communication strategies may facilitate patient illness and treatment understanding throughout the disease course. [ABSTRACT FROM AUTHOR]

Expanded implementation of genetic sequencing has precipitously increased the discovery of germline and somatic variants. The direct benefit of identifying variants in actionable genes may lead to risk reduction strategies such as increased surveillance, prophylactic surgery, as well as lifestyle modifications to reduce morbidity and mortality. However, patients with African ancestry are more likely to receive inconclusive genetic testing results due to an increased number of variants of unknown significance decreasing the utility and impact on disease management and prevention. This study examines whole exome sequencing results from germline DNA samples in African American women with a family history of cancer including 37 cases that were diagnosed with breast cancer and 51 family members. Self-identified ancestry was validated and compared to the 1000 genomes population. The analysis of sequencing results was limited to 85 genes from three clinically available common genetic screening platforms. This target region had a total of 993 variants of which 6 (<1%) were pathogenic or likely pathogenic, 736 (74.1%) were benign, and 170 (17.1%) were classified as a variant of unknown significance. There was an average of 3.4±1.8 variants with an unknown significance per individual and 85 of 88 individuals (96.6%) harbored at least one of these in the targeted genes. Pathogenic or likely pathogenic variants were only found in 6 individuals for the BRCA1 (p.R1726fs, rs80357867), BRCA2 (p.K589fs, rs397507606 & p.L2805fs, rs397507402), RAD50 (p.E995fs, rs587780154), ATM (p.V2424G, rs28904921), or MUTYH (p.G396D, rs36053993) genes. Strategies to functionally validate the remaining variants of unknown significance, especially in understudied and hereditary cancer populations, are greatly needed to increase the clinical utility and utilization of clinical genetic screening platforms to reduce cancer incidence and mortality. [ABSTRACT FROM AUTHOR]

Simple Summary: Anti-hormonal therapie regimes are well established in oncological treatments in breast cancer. In contrast there is limited knowledge of their effects on metastatic brain metastases in advanced breast cancer and their ability to cross the blood brain-barrier. In this review, we point out the usual antihormonal therapy options in the primary disease, but also in metastatic breast cancer. In addition, we explain the epidemiological facts of brain metastases, as well as the basics of the blood-brain barrier and how this is overcome by metastase. Last but not least, we deal with the known anti-hormonal therapy options and present clinical studies on their intracerebral effect, as well as the known basics of their blood-brain barrier penetration. Not all common anti-hormonal therapeutics are able to penetrate the CNS. It is therefore important for the treating oncologists to use substances that have been proven to cross the BBB, despite the limited data available. Aromataseinhibitors, especially letrozole, probably also tamoxifen, everolimus and CDK4/6 inhibitors, especially abemaciclib, appear to act intracerebrally by overcoming the blood-brain barrier. Nevertheless, further data must be obtained in basic research, but also health care research in relation to patients with brain metastases. The molecular receptor status of breast cancer has implications for prognosis and long-term metastasis. Although metastatic luminal B-like, hormone-receptor-positive, HER2−negative, breast cancer causes brain metastases less frequently than other subtypes, though tumor metastases in the brain are increasingly being detected of this patient group. Despite the many years of tried and tested use of a wide variety of anti-hormonal therapeutic agents, there is insufficient data on their intracerebral effectiveness and their ability to cross the blood-brain barrier. In this review, we therefore summarize the current state of knowledge on anti-hormonal therapy and its intracerebral impact and effects on the blood-brain barrier in breast cancer. [ABSTRACT FROM AUTHOR]

Tumor immunotherapy is considered as one of the most promising methods in cancer treatment in recent years. Immune checkpoint blockade (ICB) can activate immune cells to destroy tumors by relieving the inhibitory pathway of tumor cells to immune cells. In silico prediction of the ICB response is an important step toward achieving effective and personalized cancer immunotherapy. Although immune checkpoint inhibitors have shown exciting clinical effects in the treatment of many types of tumors, there are still some clinical problems in practical application, such as low response rate and large individualized differences. How to predict the efficacy of effective individualized immune checkpoint inhibitors for tumor patients based on specific biomarkers and computational models is one of the key issues in the immunotherapy of this kind of tumor. In our work, from the five levels of genome level, transcription level, epigenetic level, microbial taxonomy level, and the immune cell infiltration profile level, the biomarkers and in silico calculation methods that affect the efficacy of tumor immune checkpoint inhibitors are comprehensively summarized. [ABSTRACT FROM AUTHOR]

Objective: Lynch syndrome (LS) pre-screening methods remain under-investigated in colorectal cancers (CRCs) in Asia. Here, we aimed to systematically investigate LS pre-screening and comprehensively characterize LS CRCs. Methods: Microsatellite instability (MSI) and germline variants of DNA mismatch repair (MMR) genes were examined in 406 deficient MMR (dMMR) and 250 proficient MMR CRCs. The genetic differences between LS and sporadic CRCs were studied with whole exome sequencing analysis. Results: The incidence of dMMR in Chinese patients with CRCs was 13.8%. Consistency analysis between MMR immunohistochemistry (IHC) and MSI testing showed the kappa value was 0.758. With next-generation sequencing (NGS), germline variants were detected in 154 CRCs. Finally, 88 patients with CRC were identified as having LS by Sanger sequencing. Among them, we discovered 21 previously unreported pathogenic germline variants of MMR genes. Chinese patients with LS, compared with sporadic CRCs, tended to be early-onset, right-sided, early-stage and mucinous. Overall, the performance of MMR IHC and MSI testing for LS pre-screening was comparable: the area under the ROC curve for dMMR, MSI-H, and MSI-H/L was 0.725, 0.750, and 0.745, respectively. dMMR_MSI-H LS and sporadic CRCs showed substantial differences in somatic genetic characteristics, including different variant frequencies of APC, CREBBP, and KRAS, as well as different enriched pathways of VEGF, Notch, TGFβR, mTOR, ErbB, and Rac protein signal transduction. Conclusions: MMR IHC and MSI testing were effective methods for LS pre-screening. The revealed clinical and somatic genetic characteristics in LS CRCs may have the potential to improve the performance of LS pre-screening in combination with dMMR/MSI. [ABSTRACT FROM AUTHOR]

Simple Summary: Immune checkpoint inhibitors (ICIs) changed the standard care of patients with lung squamous cell carcinoma (LUSC). It is an urgent need to precisely predict the population's response to ICIs. The aim of the study was to explore novel biomarkers for LUSC immunotherapy and the potential mechanism. Five hundred and twenty-five Chinese patients with LUSC who underwent targeted sequencing were involved, and TP53 and LRP1B were the genes most frequently correlated to tumor mutational burden (TMB). Further analysis demonstrated that TP53/LRP1B co-wild was associated with improved survival of immunotherapy. Compared with those with TP53/LRP1B mutant, patients with TP53/LRP1B co-wild had lower TMB and chromosome instability, while stronger cytotoxic immune cell infiltrations, which might be the reason for the better clinical outcomes of immunotherapy. These results indicated that TP53/LRP1B co-wild might be regarded as a potential biomarker for guiding anti-PD-L1 immunotherapy in LUSC. Immunotherapy brought long-term benefits for partial patients with lung squamous cell carcinoma (LUSC). The predictor of anti-PD-L1 therapy was controversial and limited in LUSC. We aimed to explore novel biomarker for LUSC immunotherapy and the potential mechanism. Five hundred and twenty-five Chinese patients (Geneplus cohort) with LUSC underwent targeted sequencing and were involved to explore the genomic profiling. TP53 and LRP1B were the most frequently recurrent genes and correlated to higher tumor mutational burden (TMB). We observed that LUSC patients with TP53 and LRP1B co-wild (co-wild type) were associated with better survival of anti-PD-L1 therapy compared with TP53 mutant or LRP1B mutant (mutant type) in POPAR/OAK cohort. Copy-number variation (CNV) and whole genome doubling (WGD) data from TCGA LUSC cohort were obtained to assess the CNV events. There were fewer CNV alterations and lower chromosome instability in patients with TP53/LRP1B co-wild compared with those with TP53/LRP1B mutant. RNA expression data from the TCGA LUSC cohort were collected to explore the differences in RNA expression and tumor immune microenvironment (TIME) between mutant and co-wild groups. The TP53/LRP1B co-wild type had a significantly increased proportion of multiple tumor-infiltrating lymphocytes (TILs), including activated CD8 T cell, activated dendritic cell (DC), and effector memory CD8 T cell. Immune-related gene sets including checkpoint, chemokine, immunostimulatory, MHC and receptors were enriched in the co-wild type. In conclusion, TP53/LRP1B co-wild LUSC conferred an elevated response rate in anti-PD-L1 therapy and improved survival, which was associated with a chromosome-stable phenotype and an activated immune microenvironment. [ABSTRACT FROM AUTHOR]