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Accurate risk stratification is key to reducing cancer morbidity through targeted screening and preventative interventions. Multiple breast cancer risk prediction models are used in clinical practice, and often provide a range of different predictions for the same patient. Integrating information from different models may improve the accuracy of predictions, which would be valuable for both clinicians and patients. BRCAPRO is a widely used model that predicts breast cancer risk based on detailed family history information. A major limitation of this model is that it does not consider non-genetic risk factors. To address this limitation, we expand BRCAPRO by combining it with another popular existing model, BCRAT (i.e., Gail), which uses a largely complementary set of risk factors, most of them non-genetic. We consider two approaches for combining BRCAPRO and BCRAT: (1) modifying the penetrance (age-specific probability of developing cancer given genotype) functions in BRCAPRO using relative hazard estimates from BCRAT, and (2) training an ensemble model that takes BRCAPRO and BCRAT predictions as input. Using both simulated data and data from Newton-Wellesley Hospital and the Cancer Genetics Network, we show that the combination models are able to achieve performance gains over both BRCAPRO and BCRAT. In the Cancer Genetics Network cohort, we show that the proposed BRCAPRO + BCRAT penetrance modification model performs comparably to IBIS, an existing model that combines detailed family history with non-genetic risk factors.

Simple Summary: Neuroendocrine neoplasms (NENs) are occurring more frequently worldwide. Data from the UK cancer database (National Cancer Registration and Analysis Service (NCRAS)) showed that female patients have better survival with neuroendocrine neoplasms. This study used the U.S. cancer database (Surveillance, Epidemiology, and End Results Program (SEER)) to validate and compare these findings. Sixty-months survival for NENs were calculated for both male and female patients from NCRAS and SEER. The findings from NCRAS were confirmed by the findings from SEER that females survive more than males with NENs, mainly with lung and stomach NENs. The reason behind this is unclear and remains unexplained. Background: Neuroendocrine neoplasms (NENs) are increasing in incidence globally. Previous analysis of the UK cancer database (National Cancer Registration and Analysis Service (NCRAS)) showed a notable female survival advantage in most tumour sites. This study aims to compare NCRAS to the Surveillance, Epidemiology, and End Results Program (SEER) to validate these results using the same statistical methods. Methods: A total of 14,834 and 108,399 patients with NENs were extracted from NCRAS and SEER, respectively. Sixty-months survival for both males and females for each anatomical site of NENs were calculated using restricted mean survival time (RMST) and Kaplan–Meier Survival estimates. The sixty-month RMST female survival advantage (FSA) was calculated. Results: FSA was similar in NCRAS and SEER. The highest FSA occurred in lung and stomach NENs. Conclusions: The data from SEER confirm the findings published by NCRAS. Female survival advantage remains unexplained. [ABSTRACT FROM AUTHOR]

Simple Summary: Targeted biopsies of suspicious lesions detected in magnetic resonance imaging are crucial to discover clinically significant prostate cancer, especially those corresponding to index lesions. However, the optimal scheme for targeted biopsies remains unclear, despite the fact that a two- to four-core scheme is usually recommended. Saturated biopsies of the prostate gland have shown high efficiency in detecting significant PCa. In this article, we report a better efficacy for mapping using a 0.5 mm core biopsy scheme than that using the two- to four-core scheme for detecting clinically significant prostate cancer in magnetic resonance index lesions. Since the optimal scheme for targeted biopsies of magnetic resonance imaging (MRI) suspicious lesions remains unclear, we compare the efficacy of two schemes for these index lesions. A prospective trial was conducted in 1161 men with Prostate Imaging Reporting and Data System v 2.1 3–5 undergoing targeted and 12-core systematic biopsy in four centers between 2021 and 2023. Two- to four-core MRI-transrectal ultrasound fusion-targeted biopsies via the transperineal route were conducted in 900 men in three centers, while a mapping per 0.5 mm core method (saturated scheme) was employed in 261 men biopsied in another center. A propensity-matched 261 paired cases were selected for avoiding confounders other than the targeted biopsy scheme. CsPCa (grade group ≥ 2) was identified in 125 index lesions (41.1%) when the two- to four-core scheme was employed, while in 187 (71.9%) when the saturated biopsy (p < 0.001) was used. Insignificant PCa (iPCa) was detected in 18 and 11.1%, respectively (p = 0.019). Rates of csPCa and iPCa remained similar in systematic biopsies. CsPCa detected only in systematic biopsies were 5 and 1.5%, respectively (p = 0.035) in each group. The saturated scheme for targeted biopsies detected more csPCa and less iPCa than did the two- to four-core scheme in the index lesions. The rate of csPCa detected only in the systematic biopsies decreased when the saturated scheme was employed. [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]

Simple Summary: This study addresses the challenge of interpreting the efficacy of immunotherapy in biliary tract cancer (BTC) in terms of overall survival (OS). Traditional methods often rely on the proportional hazard assumption, which may not hold in this context. Instead, we performed a meta-analysis of available phase 3 trials using restricted median survival time (RMST) to measure temporal benefits, providing a clearer picture of the real effects of immunotherapy-based regimens. By incorporating anti-PD-1/anti-PD-L1 agents, our analysis confirmed improvements in estimated mean OS and progression-free survival (PFS) at 24 months, as indicated by RMST, of 1.21 (95% CI: 0.49–1.93) and 1.31 (95% CI: 0.66–1.96) months, respectively. This approach not only offers a more nuanced understanding of clinical benefits, but also aids healthcare providers and patients in making informed decisions about treatment options, emphasizing a methodology that can adapt to the complexities of data. Background: For biliary tract cancer (BTC), the addition of immunotherapy (durvalumab or pembrolizumab) to gemcitabine and cisplatin (GemCis) significantly improved overall survival (OS) in phase 3 clinical trials (RCTs). However, the interpretation and magnitude of the treatment effect is challenging because OS Kaplan–Meier curves violate the proportional hazards (PH) assumption. Analysis using restricted mean survival time (RMST) allows quantification of the benefits in the absence of PH. This systematic review and meta-analysis aims to assess the benefit of immunotherapy-based regimens for OS at 24 months using RMST analysis. Methods: A systematic review was conducted using studies published up to 8 November 2023. Only phase 3 RCTs evaluating the use of anti-PD-1/PD-L1 combined with GemCis and reporting OS were included. KM curves for OS were digitized, and the data were reconstructed. A meta-analysis for OS by RMST at 24 months was performed. Results: A total of 1754 participants from the TOPAZ-1 and KEYNOTE-966 trials were included. In TOPAZ-1, RMSTs at 24 months were 13.52 (7.92) and 12.21 (7.22) months with GemCis plus durvalumab and GemCis alone, respectively. In KEYNOTE-966, RMSTs at 24 months were 13.60 (7.76) and 12.45 (7.73) months with GemCis plus pembrolizumab and GemCis alone, respectively. Immunotherapy-based regimens showed a mean OS difference at 24 months by an RMST of 1.21 months [(95% CI: 0.49–1.93), p < 0.001, I2 = 0%]. Conclusions: Immunotherapy-based regimens improve OS in advanced BTC. Given this magnitude of benefit, it is essential to weigh up individual patient factors, preferences, and potential risks. RMST analysis provides valuable information to patients and physicians, facilitating decision-making in a value-based medical environment. [ABSTRACT FROM AUTHOR]

Simple Summary: The majority of cases of colorectal cancer occur in those over the age of 65. Treatment of colorectal cancer in older adults warrants specific considerations due to the effects of aging on comorbidities, functional and cognitive status, and socioeconomic factors. Several recent advances have been made to improve oncological outcomes and reduce toxicities with colorectal cancer treatments in both localized and metastatic disease settings. This review highlights the importance of comprehensive geriatric assessment and provides recommendations to guide the management of older adults with colorectal cancer. It summarizes prospective data from recently reported clinical trials focused on older adults. Other recommendations must at times rely on extrapolations and post hoc analyses due to the underrepresentation of older adults in colorectal cancer trials. This review should also, therefore, serve as a call to action for the field to increase the representation of this substantial and often vulnerable group of patients in future colorectal cancer trials. Colorectal cancer (CRC) poses a significant global health challenge. Notably, the risk of CRC escalates with age, with the majority of cases occurring in those over the age of 65. Despite recent progress in tailoring treatments for early and advanced CRC, there is a lack of prospective data to guide the management of older patients, who are frequently underrepresented in clinical trials. This article reviews the contemporary landscape of managing older individuals with CRC, highlighting recent advancements and persisting challenges. The role of comprehensive geriatric assessment is explored. Opportunities for treatment escalation/de-escalation, with consideration of the older adult's fitness level. are reviewed in the neoadjuvant, surgical, adjuvant, and metastatic settings of colon and rectal cancers. Immunotherapy is shown to be an effective treatment option in older adults who have CRC with microsatellite instability. Promising new technologies such as circulating tumor DNA and recent phase III trials adding later-line systemic therapy options are discussed. Clinical recommendations based on the data available are summarized. We conclude that deliberate efforts to include older individuals in future colorectal cancer trials are essential to better guide the management of these patients in this rapidly evolving field. [ABSTRACT FROM AUTHOR]

Simple Summary: Multiplex digital spatial profiling is a newly emerging approach for investigating multiple RNA transcripts and proteins simultaneously in the context of intact tissue. This review describes the different spatial technologies for the study of breast cancer, providing examples of their applicability in research and clinical settings to guide diagnosis and prognosis and to inform treatment decisions. While RNA sequencing and multi-omic approaches have significantly advanced cancer diagnosis and treatment, their limitation in preserving critical spatial information has been a notable drawback. This spatial context is essential for understanding cellular interactions and tissue dynamics. Multiplex digital spatial profiling (MDSP) technologies overcome this limitation by enabling the simultaneous analysis of transcriptome and proteome data within the intact spatial architecture of tissues. In breast cancer research, MDSP has emerged as a promising tool, revealing complex biological questions related to disease evolution, identifying biomarkers, and discovering drug targets. This review highlights the potential of MDSP to revolutionize clinical applications, ranging from risk assessment and diagnostics to prognostics, patient monitoring, and the customization of treatment strategies, including clinical trial guidance. We discuss the major MDSP techniques, their applications in breast cancer research, and their integration in clinical practice, addressing both their potential and current limitations. Emphasizing the strategic use of MDSP in risk stratification for women with benign breast disease, we also highlight its transformative potential in reshaping the landscape of breast cancer research and treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: In 2020, more than 1.9 million cases of colorectal cancer (CRC) occurred, and almost 0.9 million patients died due to CRC throughout the world. There are differences in distribution and time variations in CRC between different countries. This diversity is mainly due to differences in risk factors among populations. CRC may be prevented by primary and secondary prevention methods. Primary prevention includes avoiding risk factors, e.g., alcohol consumption, and increasing protective factors, e.g., physical activity. The secondary prevention method, called CRC screening, consists of diagnosis and treatment of precancerous lesions of the colorectum. Although a large amount of evidence is available for different aspects of CRC, controversies remain regarding the most important factors and most effective control programs for CRC in different populations. In this review, we will present the most updated evidence regarding CRC's distribution, related factors, and preventive methods. Colorectal cancer (CRC) is the third most common cancer and the second most common cause of cancer mortality worldwide. There are disparities in the epidemiology of CRC across different populations, most probably due to differences in exposure to lifestyle and environmental factors related to CRC. Prevention is the most effective method for controlling CRC. Primary prevention includes determining and avoiding modifiable risk factors (e.g., alcohol consumption, smoking, and dietary factors) as well as increasing protective factors (e.g., physical activity, aspirin). Further studies, especially randomized, controlled trials, are needed to clarify the association between CRC incidence and exposure to different risk factors or protective factors. Detection and removal of precancerous colorectal lesions is also an effective strategy for controlling CRC. Multiple factors, both at the individual and community levels (e.g., patient preferences, availability of screening modalities, costs, benefits, and adverse events), should be taken into account in designing and implementing CRC screening programs. Health policymakers should consider the best decision in identifying the starting age and selection of the most effective screening strategies for the target population. This review aims to present updated evidence on the epidemiology, risk factors, and prevention of CRC. [ABSTRACT FROM AUTHOR]

Simple Summary: Goals-of-care discussions, by promoting mutual understanding between patients and clinicians, supporting decision making and facilitating care planning, have been found to reduce acute care use and cost of care downstream. However, it is not known if goals-of-care discussions have an immediate impact on the cost of the same hospital stay. In this real-world study, we examined the hospitalization cost before and after the implementation of a goals-of-care program. We found that the overall cost in unselected medical patients did not differ significantly before and after program implementation; however, the cost of hospitalization decreased significantly among ICU patients by 17% after program implementation. This study highlights the potential value-based benefit of goals-of-care programs for patients who have serious illnesses. The impact of goals-of-care programs on acute hospitalization costs is unclear. We compared the hospitalization cost in an 8-month period before implementation of a multimodal interdisciplinary goals-of-care program (1 May 2019 to 31 December 2019) to an 8-month period after program implementation (1 May 2020 to 31 December 2020). Propensity score weighting was used to adjust for differences in potential covariates. The primary outcome was total direct cost during the hospital stay for each index hospitalization. This analysis included 6977 patients in 2019 and 5964 patients in 2020. The total direct cost decreased by 3% in 2020 but was not statistically significant (ratio 0.97, 95% CI 0.92, 1.03). Under individual categories, there was a significant decrease in medical oncology (ratio 0.58, 95% CI 0.50, 0.68) and pharmacy costs (ratio 0.86, 95% CI 0.79, 0.96), and an increase in room and board (ratio 1.06, 95% CI 1.01, 1.10). In subgroup analysis, ICU patients had a significant reduction in total direct cost after program implementation (ratio 0.83, 95% CI 0.72, 0.94). After accounting for the length of ICU admission, we found that the total direct cost per hospital day was no longer different between 2019 and 2020 (ratio 0.986, 95% CI 0.92, 1.05), suggesting that shorter ICU admissions likely explained much of the observed cost savings. This study provides real-world data on how "in-the-moment" GOC conversations may contribute to reduced hospitalization costs among ICU patients. [ABSTRACT FROM AUTHOR]

Simple Summary: In a comprehensive analysis of phase 3 clinical trials, including the two FLAIR sub-studies, ECOG1912, and the CLL13 trials, we assessed the impact of first-line treatments with targeted agents (TAs), or fludarabine, cyclophosphamide, and rituximab (FCR)-based chemo-immunotherapy (CIT), on overall survival (OS) compared to age- and sex-matched individuals in the general population. TAs demonstrated a higher 5-year restricted mean survival time (RMST) (58.1 months; 95% CI: 57.4 to 58.8) compared to CIT (5-year RMST, 56.9 months; 95% CI: 56.7–58.2). Moreover, the comparison with age- and gender-matched general populations (AGMGP) suggested that TAs may mitigate CLL's impact on OS during the first five years post-treatment initiation. In contrast, CLL patients treated with FCR exhibited sustained OS differences compared to both the Italian and US AGMGP cohorts. These results support TAs as the preferred first-line treatment for younger/fit CLL patients but imply the need for a careful interpretation due to variations in patient selection criteria and clinical profiles across trials. Longer follow-up is essential to assess the survival improvement of younger CLL patients treated with TAs relative to the AGMGP. To assess the impact of first-line treatment with targeted agents (TAs) or fludarabine, cyclophosphamide, and rituximab (FCR)-based chemo-immunotherapy (CIT) on overall survival (OS) compared to age- and sex-matched individuals in the general population, we conducted an aggregated analysis of phase 3 clinical trials, including the two FLAIR sub-studies, ECOG1912, and CLL13 trials. The restricted mean survival time (RMST), an alternative measure in outcome analyses capturing OS changes over the entire history of the disease, was used to minimize biases associated with the short follow-up time of trials. Patients treated with TAs demonstrated a higher 5-year RMST (58.1 months; 95% CI: 57.4 to 58.8) compared to those treated with CIT (5-year RMST, 56.9 months; 95% CI: 56.7–58.2). Furthermore, the OS comparison of treatment groups with the AGMGP suggests that TAs may mitigate the impact of CLL on OS during the first five years post-treatment initiation. In summary, the 5-year RMST difference was −0.4 months (95% CI: −0.8 to 0.2; p = 0.10) when comparing CLL patients treated with TAs to the Italian age- and gender-matched general population (AGMGP). A similar trend was observed when CLL patients treated with TAs were compared to the US AGMGP (5-year RMST difference, 0.3 months; 95% CI: −0.1 to 0.9; p = 0.12). In contrast, CLL patients treated with FCR exhibited sustained OS differences when compared to both the Italian cohort (5-year RMST difference: −1.6 months; 95% CI: −2.4 to −0.9; p < 0.0001) and the US AGMGP cohort (5-year RMST difference: −0.9 months; 95% CI: −1.7 to −0.2; p = 0.015). Although these results support TAs as the preferred first-line treatment for younger CLL patients, it is crucial to acknowledge that variations in patient selection criteria and clinical profiles across clinical trials necessitate a cautious interpretation of these findings that should be viewed as directional and hypothesis-generating. A longer follow-up is needed to assess the survival improvement of younger CLL patients treated with TAs relative to the AGMGP. [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: Lynch syndrome (LS) stands as the predominant inherited cancer condition at present. Currently, surveillance is based on genotype-driven strategies and mostly comprises both invasive and non-invasive medical assessments for early diagnosis. Effective preventive strategies for interrupting the biological sequence of cancer development are yet to be established. Recent findings from randomized controlled trials indicate potential preventive functions of resistant starch and/or aspirin in Lynch syndrome. The use of immunogenic frameshift peptides for vaccination appears to be a promising approach for both treating and preventing Lynch syndrome-associated cancers, based on pre-clinical and early phase 1/2a studies. Background and Aims: Lynch syndrome (LS) is currently one of the most prevalent hereditary cancer conditions, accounting for 3% of all colorectal cancers and for up to 15% of those with DNA mismatch repair (MMR) deficiency, and it was one of the first historically identified. The understanding of the molecular carcinogenesis of LS tumors has progressed significantly in recent years. We aim to review the most recent advances in LS research and explore genotype-based approaches in surveillance, personalized cancer prevention, and treatment strategies. Methods: PubMed was searched to identify relevant studies, conducted up to December 2023, investigating molecular carcinogenesis in LS, surveillance strategies, cancer prevention, and treatment in LS tumors. Results: Multigene panel sequencing is becoming the benchmark in the diagnosis of LS, allowing for the detection of a pathogenic constitutional variant in one of the MMR genes. Emerging data from randomized controlled trials suggest possible preventive roles of resistant starch and/or aspirin in LS. Vaccination with immunogenic frameshift peptides appears to be a promising approach for both the treatment and prevention of LS-associated cancers, as evidenced by pre-clinical and preliminary phase 1/2a studies. Conclusions: Although robust diagnostic algorithms, including prompt testing of tumor tissue for MMR defects and referral for genetic counselling, currently exist for suspected LS in CRC patients, the indications for LS screening in cancer-free individuals still need to be refined and standardized. Investigation into additional genetic and non-genetic factors that may explain residual rates of interval cancers, even in properly screened populations, would allow for more tailored preventive strategies. [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: The evolutionary events, carcinogenesis and speciation, are presumably based on a phase of 'genome instability' caused by DNA breakage and mis-repair leading to chromosome rearrangement. Subsequently, the corresponding initial cells pass bottlenecks of selection, yielding either a tumor or an organism with a balanced genome, structurally different from the ancestral one. It is argued that carcinogenesis and speciation are evolutionary events which are based on changes in the 'karyotypic code' through a phase of 'genome instability', followed by a bottleneck of selection for the viability and adaptability of the initial cells. Genomic (i.e., chromosomal) instability is caused by (massive) DNA breakage and the subsequent mis-repair of DNA double-strand breaks (DSBs) resulting in various chromosome rearrangements. Potential tumor cells are selected for rapid somatic proliferation. Cells eventually yielding a novel species need not only to be viable and proliferation proficient, but also to have a balanced genome which, after passing meiosis as another bottleneck and fusing with an identical gamete, can result in a well-adapted organism. Such new organisms should be genetically or geographically isolated from the ancestral population and possess or develop an at least partial sexual barrier. [ABSTRACT FROM AUTHOR]

Simple Summary: The increasing global cancer burden is intensifying health disparities, especially in low- and middle-income countries (LMICs), where access to advanced treatments is limited. A notable challenge in these regions is the scarcity of radiation therapy services, crucial for cancer treatment. This research review explores hypofractionated radiotherapy (HRT) and ultra-hypofractionated/stereotactic body radiation therapy (SBRT) as promising alternatives, offering shorter treatment durations and optimizing the use of radiotherapy machines. These methods are particularly beneficial for LMICs, addressing the growing demand for cancer care. This review provides updated clinical evidence and guidelines for applying HRT and SBRT in treating various cancers, highlighting the need for rigorous training, advanced technology, and strict safety protocols. It also emphasizes the importance of comprehensive support and collaboration to enhance access to these advanced cancer treatments in resource-limited settings. The global cancer burden, especially in low- and middle-income countries (LMICs), worsens existing disparities, amplified by the rising costs of advanced treatments. The shortage of radiation therapy (RT) services is a significant issue in LMICs. Extended conventional treatment regimens pose significant challenges, especially in resource-limited settings. Hypofractionated radiotherapy (HRT) and ultra-hypofractionated/stereotactic body radiation therapy (SBRT) offer promising alternatives by shortening treatment durations. This approach optimizes the utilization of radiotherapy machines, making them more effective in meeting the growing demand for cancer care. Adopting HRT/SBRT holds significant potential, especially in LMICs. This review provides the latest clinical evidence and guideline recommendations for the application of HRT/SBRT in the treatment of breast, prostate, and lung cancers. It emphasizes the critical importance of rigorous training, technology, stringent quality assurance, and safety protocols to ensure precise and secure treatments. Additionally, it addresses practical considerations for implementing these treatments in LMICs, highlighting the need for comprehensive support and collaboration to enhance patient access to advanced cancer care. [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]

Simple Summary: Thrombotic events are a common problem for lung cancer patients. Compared to other types of cancer, lung cancer patients are more likely to experience blood clots at any stage of their disease. Some newer cancer treatments, like immunotherapy, can also raise the risk of thrombosis. Two different categories of drugs that prevent the formation of blood clots, low-molecular-weight heparins (LMWHs) and direct oral anticoagulants (DOACs), have similar benefits in walking patients. The choice of which drug to use and when should be personalized based on the characteristics of the patient, the type of lung cancer, as well as recent treatments, such as surgery, chemotherapy or immunotherapy. The use of models that aim to predict the risk of blood clots for each patient may help physicians choose when to start treatment with anticoagulation drugs. Cancer-associated thrombosis (CAT) is a common complication in lung cancer patients. Lung cancer confers an increased risk of thrombosis compared to other solid malignancies across all stages of the disease. Newer treatment agents, including checkpoint immunotherapy and targeted agents, may further increase the risk of CAT. Different risk-assessment models, such as the Khorana Risk Score, and newer approaches that incorporate genetic risk factors have been used in lung cancer patients to evaluate the risk of thrombosis. The management of CAT is based on the results of large prospective trials, which show similar benefits to low-molecular-weight heparins (LMWHs) and direct oral anticoagulants (DOACs) in ambulatory patients. The anticoagulation agent and duration of therapy should be personalized according to lung cancer stage and histology, the presence of driver mutations and use of antineoplastic therapy, including recent curative lung surgery, chemotherapy or immunotherapy. Treatment options should be evaluated in the context of the COVID-19 pandemic, which has been shown to impact the thrombotic risk in cancer patients. This review focuses on the epidemiology, pathophysiology, risk factors, novel predictive scores and management of CAT in patients with active lung cancer, with a focus on immune checkpoint inhibitors. [ABSTRACT FROM AUTHOR]

Simple Summary: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with high mortality. Most patients present with an advanced stage of the disease, highlighting the urgent need for early detection. Recent studies of individuals at high risk of PDAC showed benefits from participating in clinical management and surveillance programs. PDAC clinical management and surveillance programs are suggested for individuals with a germline pathogenic variant in a cancer predisposition gene or a strong family history. In the present study, we performed a systematic literature review to investigate the mutational portrait of the main genes (ATM, BRCA1, BRCA2, CDKN2A, EPCAM, MLH1, MSH2, MSH6, PALB2, PMS2, STK11, TP53) involved in PDAC susceptibility. Our findings may support the development of tailored management and follow-up strategies in PDAC patients with specific germline genetic variants. Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal malignancies worldwide. While population-wide screening recommendations for PDAC in asymptomatic individuals are not achievable due to its relatively low incidence, pancreatic cancer surveillance programs are recommended for patients with germline causative variants in PDAC susceptibility genes or a strong family history. In this study, we sought to determine the prevalence and significance of germline alterations in major genes (ATM, BRCA1, BRCA2, CDKN2A, EPCAM, MLH1, MSH2, MSH6, PALB2, PMS2, STK11, TP53) involved in PDAC susceptibility. We performed a systematic review of PubMed publications reporting germline variants identified in these genes in PDAC patients. Overall, the retrieved articles included 1493 PDAC patients. A high proportion of these patients (n = 1225/1493, 82%) were found to harbor alterations in genes (ATM, BRCA1, BRCA2, PALB2) involved in the homologous recombination repair (HRR) pathway. Specifically, the remaining PDAC patients were reported to carry alterations in genes playing a role in other cancer pathways (CDKN2A, STK11, TP53; n = 181/1493, 12.1%) or in the mismatch repair (MMR) pathway (MLH1, MSH2, MSH6, PMS2; n = 87/1493, 5.8%). Our findings highlight the importance of germline genetic characterization in PDAC patients for better personalized targeted therapies, clinical management, and surveillance. [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]

Simple Summary: Several risk prediction tools have been developed to better stratify women according to their risk of developing breast cancer (BC) and inform prevention and early detection strategies. Many recent versions of these tools now incorporate a polygenic risk score (PRS) that uses the aggregated effect of common genetic variants, also known as single nucleotide polymorphisms (SNP), as a reliable predictor to estimate BC risk. However, the characteristics of each tool in terms of PRS development, population, and risk factors included vary considerably, which may affect their predictive performance and limit their use in public health practices. Thus, this systematic review characterizes BC risk prediction tools incorporating a PRS and explores the factors that can influence their ability to predict a woman's risk of developing BC during her lifetime. Single nucleotide polymorphisms (SNPs) in the form of a polygenic risk score (PRS) have emerged as a promising factor that could improve the predictive performance of breast cancer (BC) risk prediction tools. This study aims to appraise and critically assess the current evidence on these tools. Studies were identified using Medline, EMBASE and the Cochrane Library up to November 2022 and were included if they described the development and/ or validation of a BC risk prediction model using a PRS for women of the general population and if they reported a measure of predictive performance. We identified 37 articles, of which 29 combined genetic and non-genetic risk factors using seven different risk prediction tools. Most models (55.0%) were developed on populations from European ancestry and performed better than those developed on populations from other ancestry groups. Regardless of the number of SNPs in each PRS, models combining a PRS with genetic and non-genetic risk factors generally had better discriminatory accuracy (AUC from 0.52 to 0.77) than those using a PRS alone (AUC from 0.48 to 0.68). The overall risk of bias was considered low in most studies. BC risk prediction tools combining a PRS with genetic and non-genetic risk factors provided better discriminative accuracy than either used alone. Further studies are needed to cross-compare their clinical utility and readiness for implementation in public health practices. [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]

Simple Summary: Immunotherapy has become a very important treatment against several types of cancer. The clinical trials of immunotherapy have shown that these treatments present us with some novel challenges in terms of the methodology required to assess their efficacy and safety. In this article, we discuss what we consider to be the most important among those challenges and provide some suggestions to address them in the design and analysis of clinical trials of immunotherapy, especially with the class of treatments named "checkpoint inhibitors". In summary, the methodological aspects discussed in this article refer to definitions and implementation of efficacy endpoints, the evaluation of safety, and specific statistical issues that may require special attention in these trials. Immunotherapy with checkpoint inhibitors (CPIs) and cell-based products has revolutionized the treatment of various solid tumors and hematologic malignancies. These agents have shown unprecedented response rates and long-term benefits in various settings. These clinical advances have also pointed to the need for new or adapted approaches to trial design and assessment of efficacy and safety, both in the early and late phases of drug development. Some of the conventional statistical methods and endpoints used in other areas of oncology appear to be less appropriate in immuno-oncology. Conversely, other methods and endpoints have emerged as alternatives. In this article, we discuss issues related to trial design in the early and late phases of drug development in immuno-oncology, with a focus on CPIs. For early trials, we review the most salient issues related to dose escalation, use and limitations of tumor response and progression criteria for immunotherapy, the role of duration of response as an endpoint in and of itself, and the need to conduct randomized trials as early as possible in the development of new therapies. For late phases, we discuss the choice of primary endpoints for randomized trials, review the current status of surrogate endpoints, and discuss specific statistical issues related to immunotherapy, including non-proportional hazards in the assessment of time-to-event endpoints, alternatives to the Cox model in these settings, and the method of generalized pairwise comparisons, which can provide a patient-centric assessment of clinical benefit and be used to design randomized trials. [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]

Simple Summary: Recent advances in treating elderly patients with chronic lymphocytic leukemia (CLL) have emphasized the importance of geriatric assessment (GA) to evaluate patient fitness and predict treatment outcomes. Targeted therapies (BTK inhibitors and venetoclax) have demonstrated significant clinical benefits and are now a reality in CLL treatment. They have a different toxicity profile that may affect frailty. Therefore, incorporating GA before treatment initiation, considering physical and cognitive function, emotional health, comorbidity, polypharmacy, nutrition, and social support, is essential. Chronic lymphocytic leukemia (CLL) is a disease of the elderly, but chronological age does not accurately discriminate frailty status at the inter-individual level. Frailty describes a person's overall resilience. Since CLL is a stressful situation, it is relevant to assess the patient´s degree of frailty, especially before starting antineoplastic treatment. We are in the era of targeted therapies, which have helped to control the disease more effectively and avoid the toxicity of chemo (immuno) therapy. However, these drugs are not free of side effects and other aspects arise that should not be neglected, such as interactions, previous comorbidities, or adherence to treatment, since most of these medications are taken continuously. The challenge we face is to balance the risk of toxicity and efficacy in a personalized way and without forgetting that the most frequent cause of death in CLL is related to the disease. For this purpose, comprehensive geriatric assessment (GA) provides us with the opportunity to evaluate multiple domains that may affect tolerance to treatment and that could be improved with appropriate interventions. In this review, we will analyze the state of the art of GA in CLL through the five Ws. [ABSTRACT FROM AUTHOR]

Simple Summary: Single-cell RNA sequencing has significantly contributed to the discovery of heterogenous cellular programs that are highly expressed by distinct cell subtypes. Yet, the quantification of cell subtype-specific and shared gene co-expressing modules (GEMs) associated with cell differentiation is a challenge. Herein, we have developed scGEM to uncover such hidden GEMs and conducted a systematic evaluation of model performance as well as a comparison with existing methods. We demonstrate that scGEM has the potential to generate a better biological explanation of GEMs using simulated and real-world datasets. The positive impacts of this study can illuminate the interpretation of gene modules in single-cell transcriptome analysis and shed light on the cell–cell communication and regulatory network. Background: Single-cell transcriptome analysis has fundamentally changed biological research by allowing higher-resolution computational analysis of individual cells and subsets of cell types. However, few methods have met the need to recognize and quantify the underlying cellular programs that determine the specialization and differentiation of the cell types. Methods: In this study, we present scGEM, a nested tree-structured nonparametric Bayesian model, to reveal the gene co-expression modules (GEMs) reflecting transcriptome processes in single cells. Results: We show that scGEM can discover shared and specialized transcriptome signals across different cell types using peripheral blood mononuclear single cells and early brain development single cells. scGEM outperformed other methods in perplexity and topic coherence (p < 0.001) on our simulation data. Larger datasets, deeper trees and pre-trained models are shown to be positively associated with better scGEM performance. The GEMs obtained from triple-negative breast cancer single cells exhibited better correlations with lymphocyte infiltration (p = 0.009) and the cell cycle (p < 0.001) than other methods in additional validation on the bulk RNAseq dataset. Conclusions: Altogether, we demonstrate that scGEM can be used to model the hidden cellular functions of single cells, thereby unveiling the specialization and generalization of transcriptomic programs across different types of cells. [ABSTRACT FROM AUTHOR]

Simple Summary: Immune checkpoint blockades (ICBs) therapy has produced durable clinical responses in many cancer types, but only a fraction of patients can benefit from ICB treatment. Previous studies have reported multiple transcriptomic biomarkers to predict ICB responses and improve treatment precision in various cancer types. However, a timely and unbiased assessment of these biomarkers has yet to be conducted due to the lack of large-scale uniformly curated ICB-treated datasets. To address the needs, we developed ICB-Portal, a comprehensive resource about ICB including RNA-seq data of 29 datasets from public sources and standardized metadata of each study through a uniform pre-processing, 48 biomarker scores associated with ICB response, results of a systematic benchmark analysis evaluating the efficacy, and generalization ability for each biomarker in various scenarios such as different cancer types, anti-bodies, biopsy time, and combinatory treatments with other drugs by a standardized bioinformatics workflow and an online benchmark platform. Immune checkpoint blockades (ICBs) have revolutionized cancer therapy by inducing durable clinical responses, but only a small percentage of patients can benefit from ICB treatments. Many studies have established various biomarkers to predict ICB responses. However, different biomarkers were found with diverse performances in practice, and a timely and unbiased assessment has yet to be conducted due to the complexity of ICB-related studies and trials. In this study, we manually curated 29 published datasets with matched transcriptome and clinical data from more than 1400 patients, and uniformly preprocessed these datasets for further analyses. In addition, we collected 39 sets of transcriptomic biomarkers, and based on the nature of the corresponding computational methods, we categorized them into the gene-set-like group (with the self-contained design and the competitive design, respectively) and the deconvolution-like group. Next, we investigated the correlations and patterns of these biomarkers and utilized a standardized workflow to systematically evaluate their performance in predicting ICB responses and survival statuses across different datasets, cancer types, antibodies, biopsy times, and combinatory treatments. In our benchmark, most biomarkers showed poor performance in terms of stability and robustness across different datasets. Two scores (TIDE and CYT) had a competitive performance for ICB response prediction, and two others (PASS-ON and EIGS_ssGSEA) showed the best association with clinical outcome. Finally, we developed ICB-Portal to host the datasets, biomarkers, and benchmark results and to implement the computational methods for researchers to test their custom biomarkers. Our work provided valuable resources and a one-stop solution to facilitate ICB-related research. [ABSTRACT FROM AUTHOR]

Simple Summary: Approximately 20% of colorectal cancer (CRC) cases are diagnosed in individuals under 40, with a severe prognosis due to germline variant accumulation. Many of these variants have been classified as hereditary cancer causative, while others remain poorly researched. The identification of germline variants across different populations is critical for accurate prognosis, treatment, and follow-up. We aimed to identify and predict the functional implications of germline variants using whole-genome sequencing of a Tunisian pedigree with Lynch syndrome CRC risk. Two SNPs/indels were identified in genes with CRC association (MLH1 and PRH1-TAS2R14) and four in genes with non-CRC cancer association (PPP1R13B, LAMA5, FTO, and NLRP14). Three structural variants overlapped genes associated with non-CRC digestive cancer (RELN, IRS2, and FOXP1) and one overlapped RRAS2 with non-CRC cancer associations. This study provides further evidence of genetic predisposition according to the risk clustering of variants based on their functional implications and risk mechanisms within the same pedigree. Recently, worldwide incidences of young adult aggressive colorectal cancer (CRC) have rapidly increased. Of these incidences diagnosed as familial Lynch syndrome (LS) CRC, outcomes are extremely poor. In this study, we seek novel familial germline variants from a large pedigree Tunisian family with 12 LS-affected individuals to identify putative germline variants associated with varying risk of LS. Whole-genome sequencing analysis was performed to identify known and novel germline variants shared between affected and non-affected pedigree members. SNPs, indels, and structural variants (SVs) were computationally identified, and their oncological influence was predicted using the Genetic Association of Complex Diseases and Disorders, OncoKB, and My Cancer Genome databases. Of 94 germline familial variants identified with predicted functional impact, 37 SNPs/indels were detected in 28 genes, 2 of which (MLH1 and PRH1-TAS2R14) have known association with CRC and 4 others (PPP1R13B, LAMA5, FTO, and NLRP14) have known association with non-CRC cancers. In addition, 48 of 57 identified SVs overlap with 43 genes. Three of these genes (RELN, IRS2, and FOXP1) have a known association with non-CRC digestive cancers and one (RRAS2) has a known association with non-CRC cancer. Our study identified 83 novel, predicted functionally impactful germline variants grouped in three "variant risk clusters" shared in three familiarly associated LS groups (high, intermediate and low risk). This variant characterization study demonstrates that large pedigree investigations provide important evidence supporting the hypothesis that different "variant risk clusters" can convey different mechanisms of risk and oncogenesis of LS-CRC even within the same pedigree. [ABSTRACT FROM AUTHOR]

Simple Summary: Lynch syndrome is an autosomal dominant hereditary disease that confers a high risk of developing various types of tumors, especially colorectal and endometrial cancer. In recent years, the molecular mechanisms underlying Lynch syndrome have generated considerable interest. Several studies have highlighted the epiphenomenon of microsatellite instability, caused by a deficit in the ability of cells to repair DNA damage, as a disease-specific feature. The discovery of microRNAs has served to clarify how these small oligonucleotide molecules may contribute to the progression of Lynch syndrome by modulating the expression of several players involved in DNA repair pathways. The purpose of this review is to analyze the management of patients with Lynch syndrome by emphasizing the importance of microRNAs as markers or therapeutics for the development of novel clinical approaches. Lynch syndrome (LS), also known as Hereditary Non-Polyposis Colorectal Cancer (HNPCC), is an autosomal dominant cancer syndrome which causes about 2–3% of cases of colorectal carcinoma. The development of LS is due to the genetic and epigenetic inactivation of genes involved in the DNA mismatch repair (MMR) system, causing an epiphenomenon known as microsatellite instability (MSI). Despite the fact that the genetics of the vast majority of MSI-positive (MSI+) cancers can be explained, the etiology of this specific subset is still poorly understood. As a possible new mechanism, it has been recently demonstrated that the overexpression of certain microRNAs (miRNAs, miRs), such as miR-155, miR-21, miR-137, can induce MSI or modulate the expression of the genes involved in LS pathogenesis. MiRNAs are small RNA molecules that regulate gene expression at the post-transcriptional level by playing a critical role in the modulation of key oncogenic pathways. Increasing evidence of the link between MSI and miRNAs in LS prompted a deeper investigation into the miRNome involved in these diseases. In this regard, in this study, we discuss the emerging role of miRNAs as crucial players in the onset and progression of LS as well as their potential use as disease biomarkers and therapeutic targets in the current view of precision medicine. [ABSTRACT FROM AUTHOR]

Simple Summary: Lynch syndrome accounts for 2–3% of all CRC cases. This retroactive and prospective study aimed to estimate the prevalence of Lynch syndrome and describe disease-causing variants in mismatch repair genes in a diagnostic setting and in the Estonian general population. For that, ten years (2012–2022) of data was gathered. In addition, a pilot study for estimating the improvement of Lynch syndrome diagnostics by raising the age limit of mismatch repair gene immunohistochemistry was conducted. We estimated the birth prevalence of LS in Estonia at 1:8638 (95% CI: 1:9859–7588) or 11.58 (95% CI: 10.14–13.18) for 100,000 LBs between 1930 and 2003. The prevalence of Lynch syndrome has increased approximately six-fold in ten years. Due to the improvement of awareness in families and patients sharing information with their family members, the latter receives the diagnosis eight years earlier when most individuals are still healthy, illustrating the benefit of genetic testing and therefore an opportunity for prevention. Furthermore, the pilot study proved to be beneficial. Background: Lynch syndrome (LS) is the most frequent genetically pre-disposed colorectal cancer (CRC) syndrome, accounting for 2–3% of all CRC cases. In Estonia, ~1000 new cases are diagnosed each year. This retroactive and prospective study aimed to estimate the prevalence of LS and describe disease-causing variants in mismatch repair (MMR) genes in a diagnostic setting and in the Estonian general population. Methods: LS data for the diagnostic cohort were gathered from 2012 to 2022 and data for the general population were acquired from the Estonian Biobank (EstBB). Furthermore, we conducted a pilot study to estimate the improvement of LS diagnostic yield by raising the age limit to >50 years for immunohistochemistry analysis of MMR genes. Results: We estimated LS live birth prevalence between 1930 and 2003 in Estonia at 1:8638 (95% CI: 1: 9859–7588). During the study period, we gathered 181 LS individuals. We saw almost a six-fold increase in case prevalence, probably deriving from better health awareness, improved diagnostic possibilities and the implementation of MMR IHC testing in a broader age group. Conclusion: The most common genes affected in the diagnostic and EstBB cohorts were MLH1 and PMS2 genes, respectively. The LS diagnosis mean age was 44.8 years for index cases and 36.8 years (p = 0.003) for family members. In the MMR IHC pilot study, 29% had LS. [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]

Simple Summary: In this review, the authors will discuss the highlights of early onset colon cancer (EOCRC), an increasing but still unclear phenomenon. Indeed, the risk factors are largely similar to classic colon cancer (CRC), but it is still unclear what causes an increased risk of CRC at an early age. In addition, the issue of screening, which allows early diagnosis of the disease, is also important; the younger segment of the population is not included in such programs except if they belong to the highest-risk groups. If the phenomenon of EOCRC becomes more prominent, screening programs will have to be reviewed but with consideration of the consequences for health economics. In this review, we will focus on the epidemiological, prognostic, clinico-pathological, molecular, and therapeutic features of EOCRC; in particular, we will try to highlight the characteristics of the metastatic stage and the differences with CRC in older segments of the population. Despite a recent overall decrease in colorectal cancer (CRC) incidence and mortality, there has been a significant rise in CRC diagnoses in young adults. Early onset colorectal cancer (EOCRC) is defined as CRC diagnosed before the age of 50. Possible predisposing conditions include not only genetic syndromes but also other risk factors, such as microbiome alteration, antibiotic exposure, obesity, diabetes mellitus, and inflammatory bowel disease. EOCRC tends to be diagnosed later than in the older counterpart because of a lack of awareness and the fact that screening for CRC usually starts at the age of 50. Furthermore, CRC in young adults seems to be related to unique molecular features and more aggressive clinical behavior. This paper aims to provide an in-depth review of this poorly understood subject, with a comprehensive review of the state of the art and considerations for future perspectives. [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]

Simple Summary: Early-onset colorectal cancer is increasing in incidence in the United States, and it is expected to more than double in the next 10 years. There are many risk factors that lead to the development of early-onset colorectal cancer, including hereditary cancer syndromes, such as Lynch syndrome, obesity, diet, sedentary lifestyle, inflammatory bowel disease and altered microbiome. There is a significant lack of awareness of early-onset colorectal cancer, and the rise in the number of cases indicates that more coordinated efforts are needed to understand and treat early-onset colorectal cancer better, through promoting the benefits of screening, including genetic profiling, and increasing adherence to current screening guidelines. The aim of this review is to discuss the available literature regarding early-onset colorectal cancer to better define the risk factors, histopathology, genetic makeup and management. Over the past decade, the incidence of colorectal cancer has increased in individuals under the age of 50 years. Meanwhile, the incidence has gradually decreased in the older population. As described herein, we reviewed the available literature to summarize the current landscape of early-onset colorectal cancer, including risk factors, clinicopathological presentation, genetic makeup of patients, and management. Currently, early-onset colorectal cancer is treated similarly as late-onset colorectal cancer, yet the available literature shows that early-onset colorectal cancer is more aggressive and different, and this remains a significant unmet need. A detailed understanding of early-onset colorectal cancer is needed to identify risk factors for the increased incidence and tailor treatments accordingly. [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]

Simple Summary: Cancers in the urinary bladder and kidney are common in men and rarer in women. Cigarette smoking is a shared risk factor for both of these cancers. Some 50 years ago, survival in these cancers was low, and it was worse for kidney than bladder cancer. In the present study, we could show improvement in survival for these cancers in the Nordic countries, and similar improvements have also been observed in other countries. Kidney cancer survival improved remarkably well, as 50 years ago, only 20–30% of the patients survived 5 years, but currently, some 75% survive 5 years. In male bladder cancer, 5-year survival is still somewhat better than survival in kidney cancer, but female kidney cancer survival has caught up with that of bladder cancer. The reasons for this positive development for both of these cancers is earlier diagnosis as patients with blood in urine are readily taken for examinations. Additionally, treatment has become more efficient, and continuously new medications are being introduced. Kidney and bladder cancers share etiology and relatively good recent survival, but long-term studies are rare. We analyzed survival for these cancers in Denmark, Finland, Norway (NO), and Sweden (SE) over a 50-year period (1971–2020). Relative 1- and 5-year survival data were obtained from the NORDCAN database, and we additionally calculated conditional 5/1-year survival. In 2016–2020, 5-year survivals for male kidney (79.0%) and bladder (81.6%) cancers were best in SE. For female kidney cancer, NO survival reached 80.0%, and for bladder cancer, SE survival reached 76.1%. The magnitude of 5-year survival improvements during the 50-year period in kidney cancer was over 40% units; for bladder cancer, the improvement was over 20% units. Survival in bladder cancer was worse for women than for men, particularly in year 1. In both cancers, deaths in the first year were approximately as many as in the subsequent 4 years. We could document an impressive development for kidney cancer with tripled male and doubled female 5-year survival in 50 years. Additionally, for bladder cancer, a steady improvement was recorded. The current challenges are to curb early mortality and target treatment to reduce long-term mortality. [ABSTRACT FROM AUTHOR]

Simple Summary: Hepatocellular carcinoma (HCC) is the most common primary liver cancer, and despite best efforts to stratify patients recurrence remains a major issue. Our study attempted to identify what variables are involved in recurrence of HCC after resection and if they be used to stratify an individual patient's risk of recurrence. We developed a simple-to-implement RESected Tumor Outcome and Recurrence (RESTORE) index comprising three commonly assessed variables: alpha-fetoprotein level, vascular invasion, and tumor burden. The RESTORE index was highly predictive of HCC recurrence risk after resection. The RESTORE index will help identify patients who would potentially benefit from more intensive post-resection surveillance or adjuvant therapeutics. Although many variables have been associated with increased risk of hepatocellular carcinoma (HCC) recurrence after resection, no simple-to-implement risk score has been developed to determine this post-resection risk. Objective: We aimed to identify risk factors for HCC recurrence and develop a risk score for predicting recurrence of HCC in patients who undergo resection with curative intent. Design: Single-center retrospective analysis Setting: Single-center tertiary care referral hospital (University of San Francisco, California). Participants: Patients who underwent resection with curative intent for HCC between January 2005 and May 2019 with complete pathologic findings and recorded follow up. Main Outcomes and Measures: Univariate and multivariate Cox regression analysis were used to identify independent risk factors for HCC recurrence. A multivariable Cox proportional-hazard regression model with listwise deletion was used to create a risk score. Results: A total of 179 patients were included in the study; 129 (72.9%) were men, and the median (IQR) age was 63 (57–67) years. Median alpha-fetoprotein (AFP) was 12.3 ng/mL at time of resection. Most patients (82%) had a single tumor nodule, and the mean aggregate nodule size was 6.75 cm; 28.4% had evidence of vascular invasion. On multivariable Cox proportional-hazards regression, AFP ≥1000 ng/mL, multinodularity, and vascular invasion were independently associated with HCC recurrence. The RESTORE index was created using stratified pre-operative AFP, vascular invasion, and the presence of a single lesion within or beyond Milan Criteria versus multiple lesions. The RESTORE index ranged from 0–9 (highest patient score was 8) and was highly predictive of HCC recurrence (C statistic 0.70). RESTORE could stratify 5-year post-resection HCC recurrence risk, ranging from less than 25% with a score of 0 to more than 80% with a score of 5–8. Conclusions and Relevance: The RESTORE index that we developed and validated is a simple-to-implement and novel risk score for patients undergoing resection for HCC and may help identify those who would benefit most from intensive surveillance strategies or adjuvant therapies. [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]

Simple Summary: Immunotherapy has revolutionized cancer care across different cancer types. Unfortunately, leiomyosarcoma does not seem sensitive to the first-generation immune-based therapies. In this review, we present the results of trials of immunotherapy in leiomyosarcoma, emphasizing differences in results between soft-tissue leiomyosarcomas and uterine leiomyosarcomas. Then, we discuss the different molecular subgroups of leiomyosarcomas and how molecular alterations may impact response to immune checkpoint blockade. Based on these molecular descriptions, we propose some future directions to improve response rate of immunotherapy in leiomyosarcoma patients, through (1) better characterization of the immune microenvironment of different leiomyosarcoma molecular subtypes, (2) combination treatments of immunotherapy with therapies targeting specific molecular alterations, (3) new generations of immune-based therapies targeting other components of the immune microenvironment (macrophages). Leiomyosarcoma (LMS) is a rare, aggressive mesenchymal tumor with smooth muscle differentiation. LMS is one of the most common histologic subtypes of soft tissue sarcoma; it most frequently occurs in the extremities, retroperitoneum, or uterus. LMS often demonstrates aggressive tumor biology, with a higher risk of developing distant metastatic disease than most sarcoma histologic types. The prognosis is poor, particularly in patients with uterine disease, and there is a need for the development of more effective therapies. Genetically, LMS is karyotypically complex and characterized by a low tumor mutational burden, with frequent alterations in TP53, RB1, PTEN, and DNA damage response pathways that may contribute to resistance against immune-checkpoint blockade monotherapy. The LMS immune microenvironment is highly infiltrated with tumor-associated macrophages and tumor-infiltrating lymphocytes, which may represent promising biomarkers. This review provides an overview of the clinical and pathologic behavior of both soft tissue and uterine LMS and summarizes the genomic and immune characteristics of these tumors and how they may provide opportunities for the development of biomarker-based immune therapies. [ABSTRACT FROM AUTHOR]

Simple Summary: DNA repair pathways play a crucial role in maintaining the stability of a cell's genetic material. When these pathways are defective, it can lead to genomic instability in cancer cells, which can increase their ability to stimulate an immune response. Inhibiting DNA damage response, the process that helps repair DNA damage, has been shown to increase the effectiveness of anticancer immunotherapies. In this review, we will explore how deficits in the DNA repair pathway can affect the immune system's ability to fight cancer. We will also examine clinical trials that have combined inhibition of DNA damage response with immune-oncology treatments. A better understanding of these pathways could help improve the effectiveness of cancer immunotherapies and other treatments for various types of cancer. Defects in DNA repair pathways can lead to genomic instability in multiple tumor types, which contributes to tumor immunogenicity. Inhibition of DNA damage response (DDR) has been reported to increase tumor susceptibility to anticancer immunotherapy. However, the interplay between DDR and the immune signaling pathways remains unclear. In this review, we will discuss how a deficiency in DDR affects anti-tumor immunity, highlighting the cGAS-STING axis as an important link. We will also review the clinical trials that combine DDR inhibition and immune-oncology treatments. A better understanding of these pathways will help exploit cancer immunotherapy and DDR pathways to improve treatment outcomes for various cancers. [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: This study aims to compare effectiveness and cost profile in non-small-cell lung cancer (NSCLC) patients harboring synchronous brain metastases (BMs) who received non-chemo first-line systemic therapy with or without advanced radiotherapy (aRT). A total of 177 lung cancer patients, of whom 58 were treated with systemic treatment (either TKIs or pembrolizumab) plus aRT (STRT) and 119 with systemic treatment alone, were selected. The addition of aRT to systemic treatment was associated with a significantly better OS (p = 0.020) and PFS (p = 0.041) than systemic therapy alone. The incremental cost-effectiveness ratio (ICER) value indicated an average cost of €3792 for each month of survival after STRT and confirmed clinical effectiveness but higher healthcare costs. This real-world study suggests that upfront aRT in this setting represents a valid treatment strategy, boosting the efficacy of emerging drug classes with sustainable costs for the health service. Aim: Healthcare administrative databases represent a valuable source for real-life data analysis. The primary aim of this study is to compare effectiveness and cost profile in non-small-cell lung cancer (NSCLC) patients harboring synchronous brain metastases (BMs) who received non-chemo first-line systemic therapy with or without advanced radiotherapy (aRT). Methods: Diagnostic ICD-9-CM codes were used for identifying all patients with a new diagnosis of lung cancer between 2012 and 2019. Among these, patients who had started a first-line systemic treatment with either TKIs or pembrolizumab, alone or in combination with intensity-modulated or stereotactic RT, were selected. Clinical outcomes investigated included overall survival (OS), progression-free survival (PFS), and time-to-treatment failure (TTF). The cost outcome was defined as the average per capita cumulative healthcare direct costs of the treatment, including all inpatient and outpatient costs. Results: The final cohort included 177 patients, of whom 58 were treated with systemic treatment plus aRT (STRT) and 119 with systemic treatment alone. The addition of aRT to systemic treatment was associated with a significantly better OS (p = 0.020) and PFS (p = 0.041) than systemic therapy alone. The ICER (incremental cost-effectiveness ratio) value indicated an average cost of €3792 for each month of survival after STRT treatment and confirmed clinical effectiveness but higher healthcare costs. Conclusions: This real-world study suggests that upfront aRT for NCLSC patients with synchronous BMs represents a valid treatment strategy, boosting the efficacy of novel and emerging drug classes with sustainable costs for the health service. Translational relevance: The present real-world study reports that the use of upfront advanced radiotherapyaRT and new-generation systemic agents, such as TKIs and pembrolizumab, may have higher oncological control and an improved cost-effectiveness profile than the use of new-generation systemic agents alone in NCLSC patients with synchronous brain metastases. Acquired evidence can also be used to inform policymakers that adding advanced radiotherapy results is a sustainable cost for the health service. Since approximately 50% of patients do not meet RCT inclusion criteria, a significant proportion of them is receiving treatment that is not evidence-informed; therefore, these results warrant further studies to identify the best radiotherapy timing and possible dose escalation approaches to improving treatment efficacy in patient subgroups not typically represented in randomized controlled trials. [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]

Simple Summary: Hemato-poietic stem cell transplantation is associated with significant endothelial dysfunction, which may result in severe complications. Endothelial dysfunction induces the expression of multiple substances including, cell adhesion molecules, pro-inflammatory cytokines, and coagulation factors resulting in activation of the complement system, and promoting a procoagulant and proinflammatory state. The pathophysiological process that mediates the endothelial damage is not clearly understood and the aim of this study is a comprehensive review of the existing knowledge. Moreover, the levels of soluble molecules released in the systemic circulation as a result of endothelial damage may serve as biomarkers for the early diagnosis and the pre-emptive treatment of post-transplant syndromes. The review of the existing literature presented in detail shows that the ideal biomarker with sufficient sensitivity and specificity for the early diagnosis of post-transplant complications does not currently exist. Future studies should focus on the identification of novel biomarkers with sufficient specificity and sensitivity. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only therapy with a curative potential for a variety of malignant and non-malignant diseases. The major limitation of the procedure is the significant morbidity and mortality mainly associated with the development of graft versus host disease (GVHD) as well as with a series of complications related to endothelial injury, such as sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD), transplant-associated thrombotic microangiopathy (TA-TMA), etc. Endothelial cells (ECs) are key players in the maintenance of vascular homeostasis and during allo-HSCT are confronted by multiple challenges, such as the toxicity from conditioning, the administration of calcineurin inhibitors, the immunosuppression associated infections, and the donor alloreactivity against host tissues. The early diagnosis of endothelial dysfunction syndromes is of paramount importance for the development of effective prophylactic and therapeutic strategies. There is an urgent need for the better understanding of the pathogenetic mechanisms as well as for the identification of novel biomarkers for the early diagnosis of endothelial damage. This review summarizes the current knowledge on the biology of the endothelial dysfunction syndromes after allo-HSCT, along with the respective therapeutic approaches, and discusses the strengths and weaknesses of possible biomarkers of endothelial damage and dysfunction. [ABSTRACT FROM AUTHOR]

Simple Summary: Lynch syndrome (LS) is an autosomal dominant hereditary disorder characterised by germline mutation in one of the four DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, PMS2) or deletion of the EPCAM gene. LS predisposes affected individuals to an increased lifetime risk of colorectal (30–73%), endometrial (30–51%), genitourinary cancers (2–20%) and various other malignancies. Although LS-associated upper tract urothelial carcinoma cancer has been extensively investigated, evidence surrounding the role of LS in developing bladder and kidney cancer remains scarce and inconclusive. The aim of this study was to quantify the pooled relative risk of bladder and kidney cancer, summarise the existing evidence on screening and provide a useful recommendation to guide clinicians in identifying and diagnosing at risk individuals. Background: The association between Lynch syndrome (LS) and a higher risk of upper tract urothelial carcinoma is well established, but its effect on the risk of bladder and kidney cancers remains controversial. This review aimed to compare the relative risk (RR) of bladder and kidney cancer in confirmed LS germline mutation carriers compared to the general population. Methods: Medline, Embase, Cochrane Central, and Google Scholar were searched on 14 July 2022 for studies published in English that reported on the rates of urological cancer in adults with confirmed LS germline mutation. The quality of included studies was assessed using Cochrane's tool to evaluate risk of bias in cohort studies. Random effects meta-analysis estimated the pooled relative risk of bladder and kidney cancer in LS carriers compared to the general population. The quality of the overall evidence was evaluated using GRADE. Results: Of the 1839 records identified, 5 studies involving 7120 participants from 3 continents were included. Overall, LS carriers had a statistically significantly higher RR of developing bladder cancer (RR: 7.48, 95% CI: 3.70, 15.13) and kidney cancer (RR: 3.97, 95% CI: 1.23, 12.81) compared to unaffected participants (p < 0.01). The quality of the evidence was assessed as "low" due to the inclusion of cohort studies, the substantial heterogeneity, and moderate-to-high risk of bias. Conclusion: Lynch syndrome is associated with a significant increase in the relative risk of kidney and bladder cancer. Clinicians should adopt a lower threshold for germline mutation genetic testing in individuals who present with bladder cancer. Further studies evaluating the role and cost-effectiveness of novel urine-based laboratory tests are needed. High-quality studies in histologically proven renal cell carcinoma and their underlying germline mutations are necessary to strengthen the association with LS. [ABSTRACT FROM AUTHOR]

Simple Summary: This work determines the predictive value of the consensus Immunoscore in 1885 patients with AJCC/UICC-TNM stage I-II Colon Cancer (CC) from North American, European, and Asian care centers. Herein, we demonstrate that the immunity of early-stage CC patients, more than cancer cell-associated parameters, predicts outcome for stage I/II patients. Similar results were found for high-risk patients defined based on parameters such as the grade of differentiation, T4 stage, venous emboli, lymphatic invasion or perineural invasion (VELIPI). Within these pathological risk subgroups, the consensus Immunoscore accurately identifies early-stage CC patients with different clinical outcome, without treatment bias. Thus, the Immunoscore reliably diagnoses low immune cell infiltrated patients at risk of relapse, that would benefit from a more frequent and detailed medical monitoring. The Immunoscore is a patient classification method that can guide treatment decisions, through the quantification of CD3+ and cytotoxic CD8+ T-lymphocytes densities within the tumor and its invasive margin. Background: The prognostic value of Immunoscore was evaluated in Stage II/III colon cancer (CC) patients, but it remains unclear in Stage I/II, and in early-stage subgroups at risk. An international Society for Immunotherapy of Cancer (SITC) study evaluated the pre-defined consensus Immunoscore in tumors from 1885 AJCC/UICC-TNM Stage I/II CC patients from Canada/USA (Cohort 1) and Europe/Asia (Cohort 2). METHODS: Digital-pathology is used to quantify the densities of CD3+ and CD8+ T-lymphocyte in the center of tumor (CT) and the invasive margin (IM). The time to recurrence (TTR) was the primary endpoint. Secondary endpoints were disease-free survival (DFS), overall survival (OS), prognosis in Stage I, Stage II, Stage II-high-risk, and microsatellite-stable (MSS) patients. RESULTS: High-Immunoscore presented with the lowest risk of recurrence in both cohorts. In Stage I/II, recurrence-free rates at 5 years were 78.4% (95%-CI, 74.4–82.6), 88.1% (95%-CI, 85.7–90.4), 93.4% (95%-CI, 91.1–95.8) in low, intermediate and high Immunoscore, respectively (HR (Hi vs. Lo) = 0.27 (95%-CI, 0.18–0.41); p < 0.0001). In Cox multivariable analysis, the association of Immunoscore to outcome was independent (TTR: HR (Hi vs. Lo) = 0.29, (95%-CI, 0.17–0.50); p < 0.0001) of the patient's gender, T-stage, sidedness, and microsatellite instability-status (MSI). A significant association of Immunoscore with survival was found for Stage II, high-risk Stage II, T4N0 and MSS patients. The Immunoscore also showed significant association with TTR in Stage-I (HR (Hi vs. Lo) = 0.07 (95%-CI, 0.01–0.61); P = 0.016). The Immunoscore had the strongest (69.5%) contribution χ2 for influencing survival. Patients with a high Immunoscore had prolonged TTR in T4N0 tumors even for patients not receiving chemotherapy, and the Immunoscore remained the only significant parameter in multivariable analysis. CONCLUSION: In early CC, low Immunoscore reliably identifies patients at risk of relapse for whom a more intensive surveillance program or adjuvant treatment should be considered. [ABSTRACT FROM AUTHOR]

Simple Summary: Short, dysfunctional telomeres represent the genetic biomarkers of cancer. Studies in early-stage non-small-cell lung cancer (NSCLC) have shown that telomere length and telomerase levels are correlated with survival. In patients with advanced NSCLC, telomere status has not yet been investigated, and its clinical significance remains unknown. We studied telomere length and the expression of telomerase and shelterin genes in a cohort of 79 patients with advanced NSCLC, and evaluated these parameters as potential prognostic and predictive factors. Telomere shortening, high levels of telomerase and aberrant expression of shelterin genes TRF2, RAP1 and TIN2 were significantly correlated with shorter survival. Furthermore, a worse response to immunotherapy was observed in patients with shorter telomeres. The determination of telomere parameters in advanced NSCLC could be useful for individualized treatment decisions. Telomere length appears to correlate with survival in early non-small-cell lung cancer (NSCLC), but the prognostic impact of telomere status in advanced NSCLC remains undetermined. Our purpose was to evaluate telomere parameters as prognostic and predictive biomarkers in advanced NSCLC. In 79 biopsies obtained before treatment, we analyzed the telomere length and expression of TERT and shelterin complex genes (TRF1, TRF2, POT1, TPP1, RAP1, and TIN2), using quantitative PCR. Non-responders to first-line chemotherapy were characterized by shorter telomeres and low RAP1 expression (p = 0.0035 and p = 0.0069), and tended to show higher TERT levels (p = 0.058). In multivariate analysis, short telomeres were associated with reduced event-free (EFS, p = 0.0023) and overall survival (OS, p = 0.00041). TERT and TRF2 overexpression correlated with poor EFS (p = 0.0069 and p = 0.00041) and OS (p = 0.0051 and p = 0.007). Low RAP1 and TIN2 expression-levels were linked to reduced EFS (p = 0.00032 and p = 0.0069) and OS (p = 0.000051 and p = 0.02). Short telomeres were also associated with decreased survival after nivolumab therapy (p = 0.097). Evaluation of telomere status in advanced NSCLC emerges as a useful biomarker that allows for the selection of patient groups with different clinical evolutions, to establish personalized treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: Hepatocellular carcinoma (HCC) is among the most common cancers and causes about 830,000 deaths annually in the world. Metabolic reprogramming is a critical hallmark of HCC, enabling HCC cells to adapt to the high energy demands necessary for fast growth. However, the clinical relevance of metabolic alteration in HCC has not been systematically assessed. By performing cross-species comparison of genomic data from mouse and human tissues, we identified three distinct metabolic subtypes of HCC and uncovered clinical and molecular characteristics associated with three subtypes. Importantly, we showed that the high metabolic subtype is less susceptible to immunotherapy and uncovered a potential mechanism associated with resistance to immunotherapy. High metabolic activity is a hallmark of cancers, including hepatocellular carcinoma (HCC). However, the molecular features of HCC with high metabolic activity contributing to clinical outcomes and the therapeutic implications of these characteristics are poorly understood. We aimed to define the features of HCC with high metabolic activity and uncover its association with response to current therapies. By integrating gene expression data from mouse liver tissues and tumor tissues from HCC patients (n = 1038), we uncovered three metabolically distinct HCC subtypes that differ in clinical outcomes and underlying molecular biology. The high metabolic subtype is characterized by poor survival, the strongest stem cell signature, high genomic instability, activation of EPCAM and SALL4, and low potential for benefitting from immunotherapy. Interestingly, immune cell analysis showed that regulatory T cells (Tregs) are highly enriched in high metabolic HCC tumors, suggesting that high metabolic activity of cancer cells may trigger activation or infiltration of Tregs, leading to cancer cells' evasion of anti-cancer immune cells. In summary, we identified clinically and metabolically distinct subtypes of HCC, potential biomarkers associated with these subtypes, and a potential mechanism of metabolism-mediated immune evasion by HCC cells. [ABSTRACT FROM AUTHOR]