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Simple Summary: Patients with stage IIB and IIC melanoma are considered to have high-risk localized disease and, in some cases, demonstrate worse recurrence-free and overall survival than patients with stage IIIA and even IIIB disease. The mainstay of treatment for patients with high-risk clinical stage II melanoma is surgical resection of the primary tumor and sentinel lymph node biopsy (SLNB), which confers accurate pathologic staging and prognostication for further treatment decisions. Building on the success of adjuvant therapy for stage III melanoma, the KEYNOTE-716 and CheckMate 76K trials found improved recurrence-free survival for patients with high-risk stage II melanoma with adjuvant pembrolizumab and nivolumab, respectively, after complete resection with SLNB. Given these findings, the National Comprehensive Cancer Network now recommends discussing adjuvant pembrolizumab or nivolumab with patients with high-risk stage IIB/C melanoma, weighing the risks of recurrence against the risks of treatment-related adverse events when making the decision regarding adjuvant therapy. Melanoma is the fifth most common cancer in the United States and accounts for the majority of all skin cancer-related deaths, making it the most lethal cutaneous malignancy. Systemic adjuvant therapy for stage IIB-IV melanoma is now approved for patients who have undergone surgical resection, given the appreciable risk of recurrence and mortality in this patient population. Despite the lower stage, high-risk stage II melanoma (stage IIB/IIC) can often exhibit an even more aggressive course when compared to stage IIIA/IIIB disease, thus justifying consideration of adjuvant therapy in these patients. In this review, we highlight the current standard of practice for the treatment of stage IIB/C melanoma, with a focus on adjuvant therapies supported by published landmark clinical trials, including anti-PD-1 therapy. Notably, adjuvant therapies approved thus far in this patient population have demonstrated an improvement in recurrence-free survival, while their impact on overall survival is pending. Finally, this review highlights currently ongoing trials and future directions for research and treatment possibilities for high-risk clinical stage II melanoma. [ABSTRACT FROM AUTHOR]

Simple Summary: Lung cancer treatment options vary depending on the type and stage of the cancer. For non-small cell lung cancer (NSCLC), treatments may include surgery, chemotherapy, radiation therapy, targeted therapy, or a combination of these methods. Targeted therapies have demonstrated efficacy as adjuvant treatment in early-stage NSCLC when used alongside primary interventions such as surgery. In advanced stages of NSCLC, targeted therapies serve as a means of palliative care, enhancing quality of life and extending survival time. Our review article focuses on recent evidence of various treatment approaches and their impact on overall and progression-free survival in NSCLC patients, particularly targeting specific molecular and genetic alterations associated with NSCLC. Non-small cell lung cancer (NSCLC) presents a complex and diverse disease, exhibiting variations at individuals' cellular and histological levels. This complexity gives rise to different subtypes and genetic mutations, posing challenges for accurate diagnosis and effective treatment. Nevertheless, continuous progress in medical research and therapies is continually shaping the landscape of NSCLC diagnosis and management. The treatment of NSCLC has undergone significant advancements in recent years, especially with the emergence of targeted therapies that have shown remarkable efficacy in patients with actionable mutations. This has ushered in the era of personalized medicine in NSCLC treatment, with improvements in molecular and immunohistochemical techniques contributing to enhanced progression-free survival. This review focuses on the latest progress, challenges, and future directions in developing targeted therapies for NSCLC, including tyrosine kinase inhibitors (TKIs), DNA-damaging agents, immunotherapy regimens, natural drug therapy, and nanobodies. Furthermore, recent randomized studies have demonstrated enhanced overall survival in patients receiving different targeted and natural drug therapies. [ABSTRACT FROM AUTHOR]

Simple Summary: Glioblastoma (GBM) is the most aggressive primary brain tumor. Despite intensive management with surgery, radio-, and chemotherapy, prognosis remains bleak, with a median survival of 15 months. Recently, microglia, the resident immune cells of the brain, have emerged as a potential therapeutic target for treatment of GBM. However, precisely how microglia interact with GBM cells and may be exploited for novel immunotherapies is not well understood. Here, we discuss the role of microglia in the GBM tumor microenvironment (TME), focusing particularly on the pro- and anti-tumorigenic pathways involved. We first introduce microglia and their role in the normal brain environment. Next, we discuss the microglia-GBM crosstalk, delving into specific factors that mediate these interactions. Finally, we present a comprehensive discussion of suitable microglial pathways that can be targeted to modulate the immune response in the TME to halt tumor progression. We discuss this in the context of current and past clinical trials targeting microglia, summarizing both successes and failures, and highlight promising pathways that are yet to be explored, suggesting future directions for study. Glioblastoma (GBM) is one of the most aggressive and devastating primary brain tumors, with a median survival of 15 months following diagnosis. Despite the intense treatment regimen which routinely includes maximal safe neurosurgical resection followed by adjuvant radio- and chemotherapy, the disease remains uniformly fatal. The poor prognosis associated with GBM is multifactorial owing to factors such as increased proliferation, angiogenesis, and metabolic switching to glycolytic pathways. Critically, GBM-mediated local and systemic immunosuppression result in inadequate immune surveillance and ultimately, tumor-immune escape. Microglia—the resident macrophages of the central nervous system (CNS)—play crucial roles in mediating the local immune response in the brain. Depending on the specific pathological cues, microglia are activated into either a pro-inflammatory, neurotoxic phenotype, known as M1, or an anti-inflammatory, regenerative phenotype, known as M2. In either case, microglia secrete corresponding pro- or anti-inflammatory cytokines and chemokines that either promote or hinder tumor growth. Herein, we review the interplay between GBM cells and resident microglia with a focus on contemporary studies highlighting the effect of GBM on the subtypes of microglia expressed, the associated cytokines/chemokines secreted, and ultimately, their impact on tumor pathogenesis. Finally, we explore how understanding the intricacies of the tumor-immune landscape can inform novel immunotherapeutic strategies against this devastating disease. [ABSTRACT FROM AUTHOR]

Simple Summary: In this retrospective study conducted at a tertiary cancer center, real-world outcomes from advanced melanoma patients were analyzed approximately a decade after the introduction of immune checkpoint inhibitors and BRAF/MEK-inhibitors into clinical use. The study included patients in the resectable/adjuvant (n = 331) and unresectable/metastatic setting (n = 375). Adjuvant anti-PD1 or BRAF/MEK inhibitors demonstrated 3-year relapse-free survival rates of 53% and 67.6%, respectively. Toxicity led to treatment cessation in 10.9% of cases, with no impact on relapse-free or overall survival rates unless treatment duration was <3 months. First-line treatment in the unresectable setting showed 5-year overall survival rates of 46.5% for anti-PD1, 52.4% for anti-CTLA4/PD1, and 49.2% for BRAF/MEK inhibitors. Brain metastases and elevated LDH levels substantially affected overall survival. For patients with progressive disease, the median overall survival rate dropped below two years. The study highlights real-world clinical management and outcomes of advanced melanoma patients, emphasizing the efficacy of approved treatments while addressing ongoing challenges. Background: Immune checkpoint inhibitors (ICIs) and BRAF/MEK inhibitors (BRAF/MEKi) have drastically changed the outcomes of advanced melanoma patients in both the resectable/adjuvant and unresectable/metastatic setting. In this follow-up analysis of real-world data, we aimed to investigate the clinical management and outcomes of advanced melanoma patients in a tertiary referral center in Switzerland approximately a decade after the introduction of ICIs and BRAF/MEKi into clinical use. Moreover, we aimed to compare the results with seminal phase 3 trials and to identify areas of high unmet clinical need. Methods: This single-center retrospective cohort study analyzed the melanoma registry of the University Hospital Zurich, a tertiary cancer center in Switzerland, and included patients treated in the resectable/adjuvant (n = 331) or unresectable/metastatic setting (n = 375). Results: In the resectable setting, adjuvant anti-PD1 or BRAF/MEKi showed a 3-year relapse-free survival (RFS) of 53% and 67.6%, respectively, and the overall median RFS was 50 months. Patients with lymph node plus in-transit metastases or with distant metastases prior to commencing adjuvant treatment had a significantly reduced overall survival (OS). In 10.9% of patients, the treatment was stopped due to toxicity, which did not affect RFS/OS, unless the duration of the treatment was <3 months. Following a relapse of the disease during the first adjuvant treatment, the median progression-free survival (PFS2) was only 6.6 months; outcomes were particularly poor for relapses that were unresectable (median PFS2 3.9 months) or occurred within the first 2 months (median PFS2 2.7 months). A second adjuvant treatment for patients with resectable relapses still showed efficacy (median RFS2 43.7 months). Elevated LDH levels in patients with an unresectable relapse was correlated with a strong reduction in OS2 (HR 9.84, p = 0.018). In the unresectable setting, first-line anti-PD1, anti-CTLA4/PD1 combination, or BRAF/MEKi showed a 5-year OS of 46.5%, 52.4%, and 49.2%, respectively. In a multivariate analysis, elevated LDH levels or the presence of brain metastases substantially shortened OS (HR > 1.78, p < 0.035). There was a non-significant trend for the improved survival of patients treated with anti-CTLA4/PD1 compared to anti-PD1 (HR 0.64, p = 0.15). After a progression on first-line therapy, the median OS2 was reduced to below two years. Elevated LDH (HR 4.65, p < 0.001) levels and widespread disease with at least three metastatic sites, particularly bone metastases (HR 2.62, p = 0.026), affected OS2. Conclusion: Our study offers real-world insights into the clinical management, treatment patterns, and outcomes of advanced melanoma patients in both the adjuvant and unresectable setting. Early relapses in patients undergoing adjuvant treatment pose a particular challenge but these patients are generally excluded from first-line trials. The approved first-line metastatic treatments are highly effective in the real-world setting with 5-year OS rates around 50%. However, outcomes remain poor for patients with brain metastases or who fail first-line treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: FLOT-based perioperative chemotherapy is the mainstay of treatment for patients with non-metastatic gastric cancer in Western countries. Although signet-ring cell histology has been proven to be associated with a lack of response to chemotherapy, there is a lack of data concerning whether FLOT-based chemotherapy might be less effective in patients with signet-ring histology. The aim of this retrospective study is to assess whether patients whose gastric cancer is signet-ring cell positive might benefit less compared to others when treated with perioperative FLOT. Background: FLOT perioperative chemotherapy represents the standard of care in non-metastatic gastric cancer patients. Signet-ring cell positivity is associated with a worse prognosis in patients with gastric cancer treated with chemotherapy. Comparison between FLOT perioperative chemotherapy vs. surgery followed by adjuvant chemotherapy based on signet-ring cell positivity is lacking. The aim of the analysis was to compare perioperative FLOT with adjuvant chemotherapy in gastric cancer patients stratified by signet-ring cell positivity. Methods: We conducted a retrospective multicenter analysis based on disease-free survival (DFS) and overall survival (OS) in patients with gastric cancer who received perioperative chemotherapy with a FLOT regimen and compared their survival with a historical cohort of patients treated with adjuvant chemotherapy, matched by cT and cN stage and by tumor histological features. Results: Seventy-six patients were enrolled and 24 (32%) were signet-ring cell positive. At a median follow-up time of 39 months, the median DFS was 26.3 months and the median OS was 37.3 months. Signet-ring cell positivity was associated with a shorter OS (median OS: 20.4 vs. 46.9 months, HR: 3.30, 95%CI: 1.56–6.99, p = 0.0018) and DFS (mDFS: 15.2 vs. 38.6 months, HR: 3.18, 95%CI: 1.55–6.54, p = 0.0016). This was confirmed by multivariate analysis for DFS (Exp(B): 2.55) and OS (Exp(B): 2.68). After propensity score matching, statistically significant shorter DFS (HR: 3.30, 95%CI: 1.50–7.35, p = 0.003) and OS (HR: 5.25, 95%CI: 2.18–12–68, p = 0.0002) were observed for patients with signet-ring cell positivity who received perioperative treatment vs. those who received surgery followed by adjuvant chemotherapy. Conclusions: Signet-ring positivity was associated with shorter DFS and OS in patients who received perioperative treatment with FLOT compared with surgery followed by adjuvant therapy. These data suggest that for patients with signet-ring cell histology, FLOT perioperative treatment might not always be the best choice of treatment, and further research should be focused on this group of patients. [ABSTRACT FROM AUTHOR]

Simple Summary: The incidence of cardiac morbimortality in acute myeloid leukemia (AML) is not well known. We aim to estimate the cumulative incidence (CI) of cardiac events in AML patients and to identify risk factors for their occurrence. We observed a high incidence of cardiac events (58.5%) among 525 treated patients, coupled with significant mortality due to cardiotoxicity (3.6%). The presence of relevant cardiac antecedents was the main risk factor for developing fatal cardiac events (hazard ratio (HR) = 1.9). Age ≥ 65 (HR = 2.2), relevant cardiac antecedents (HR = 1.4), and non-intensive chemotherapy (HR = 1.8) were associated with non-fatal cardiac events. We observed that, among 285 intensive therapy patients, median overall survival was decreased in those experiencing grade 3–4 cardiac events (p < 0.001). We identified prognostic factors that increase the risk of cardiac events, which may be useful in selecting high-risk patients for stringent cardiac monitoring and management. The incidence of cardiac morbimortality in acute myeloid leukemia (AML) is not well known. We aim to estimate the cumulative incidence (CI) of cardiac events in AML patients and to identify risk factors for their occurrence. Among 571 newly diagnosed AML patients, 26 (4.6%) developed fatal cardiac events, and among 525 treated patients, 19 (3.6%) experienced fatal cardiac events (CI: 2% at 6 months; 6.7% at 9 years). Prior heart disease was associated with the development of fatal cardiac events (hazard ratio (HR) = 6.9). The CI of non-fatal cardiac events was 43.7% at 6 months and 56.9% at 9 years. Age ≥ 65 (HR = 2.2), relevant cardiac antecedents (HR = 1.4), and non-intensive chemotherapy (HR = 1.8) were associated with non-fatal cardiac events. The 9-year CI of grade 1–2 QTcF prolongation was 11.2%, grade 3 was 2.7%, and no patient had grade 4–5 events. The 9-year CI of grade 1–2 cardiac failure was 1.3%, grade 3–4 was 15%, and grade 5 was 2.1%; of grade 1–2, arrhythmia was 1.9%, grade 3–4 was 9.1%, and grade 5 was 1%. Among 285 intensive therapy patients, median overall survival decreased in those experiencing grade 3–4 cardiac events (p < 0.001). We observed a high incidence of cardiac toxicity associated with significant mortality in AML. [ABSTRACT FROM AUTHOR]

Simple Summary: Precision medicine has revolutionized the treatment of advanced non-small cell lung cancer (NSCLC). Due to the discovery of novel predictive biomarkers, an exhaustive molecular characterization of the disease is required for adequate clinical management. In this research, we aim to evaluate the implementation of next-generation sequencing (NGS) in routine diagnostics under a quality management system. In a cohort of 350 patients, NGS studies were able to reveal a distinct molecular profile of the disease according to sex and smoking status, as well as co-occurring and mutually exclusive relationships between molecular alterations. In stage IV patients, targeted therapies were associated with longer progression-free and overall survival. NGS has expanded precision medicine in our center by increasing the percentage of patients with actionable molecular alterations. Our findings consolidate the use of NGS as a molecular diagnostic tool in the clinical routine of a public healthcare hospital. Next-generation sequencing (NGS) is a molecular approach able to provide a comprehensive molecular profile of non-small cell lung cancer (NSCLC). The broad spectrum of biomarker-guided therapies has positioned molecular diagnostic laboratories as a central component of patient clinical management. Here, we show the results of an UNE-EN ISO 15189:2022 NGS-accredited assay in a cohort of 350 patients. TP53 (51.0%), KRAS (26.6%) and EGFR (12.9%) were the most frequently mutated genes. Furthermore, we detected co-occurring and mutually exclusive alterations, as well as distinct molecular profiles according to sex and smoking habits. Actionable genetic alterations were significantly more frequent in female patients (80.5%, p < 0.001) and in never-smoker patients (87.7%, p < 0.001). When NGS was established as the main molecular testing strategy, 36.4% of patients received at least one line of targeted treatment. Among 200 patients with stage IV NSCLC, first-line treatment with targeted therapies was associated with a longer progression-free survival (PFS) (13.4 months (95% CI, 10.2–16.6) (p = 0.001)). Similarly, the overall survival (OS) of patients receiving at least one targeted drug was significantly longer (26.2 months (95% CI, 11.8–40.5) (p < 0.001)). Our results show that the implementation of NGS in the public healthcare system has provided a broader application of precision medicine. [ABSTRACT FROM AUTHOR]

Simple Summary: Decompensated patients with hepatocellular carcinoma (HCC) are a wide patient category with limited therapeutic options, and are often excluded from existing trials. Liver transplantation is the best treatment option for such patients but is affected by strict selection criteria and liver donor shortages. The data regarding locoregional treatments in patients with impaired liver function are scarce but indicate a possible survival benefit provided they are well tolerated. Perhaps the systemic treatments, and particularly immunotherapy, are the safest option for such patients based on the available real-life data. Regardless of the type of treatment, close adverse event monitoring is mandatory due to the high risk of hepatic disease deterioration. The aim of this review is to analyze the existing data regarding the administration of treatment in decompensated patients with HCC, evaluate the effect of therapy on overall survival, highlight the potential risks in terms of tolerability and elucidate the optimal therapeutic management. Primary liver cancer is the sixth most common cancer and the fourth leading cause of cancer-related death. Hepatocellular carcinoma (HCC) accounts for 75% of primary liver cancer cases, mostly on the basis of cirrhosis. However, the data and therapeutic options for the treatment of HCC in patients with decompensated cirrhosis are rather limited. This patient category is often considered to be in a terminal stage without the possibility of a specific treatment except liver transplantation, which is restricted by several criteria and liver donor shortages. Systemic treatments may provide a solution for patients with Child Pugh class B or C since they are less invasive. Although most of the existing trials have excluded patients with decompensated cirrhosis, there are increasing data from real-life settings that show acceptable tolerability and satisfying efficacy in terms of response. The data on the administration of locoregional treatments in such patients are also limited, but the overall survival seems to be potentially prolonged when patients are carefully selected, and close adverse event monitoring is applied. The aim of this review is to analyze the existing data regarding the administration of treatments in decompensated patients with HCC, evaluate the effect of therapy on overall survival and highlight the potential risks in terms of tolerability. [ABSTRACT FROM AUTHOR]

Simple Summary: At Istituto Oncologico Veneto we are providing a geriatric assessment to all patients aged 70 years and older since 2003. Soft tissue sarcoma are really rare neoplasm and we, as a referral centre, evaluate a high volume of patients, so we decided to conduct this study to describe the geriatric multidisciplinary management and also the role the geriatric tools in the decision making and in assessing the prognosis. Background: Incidences of soft tissue sarcomas (STS) steadily increase with age. Yet, despite the high prevalence in advanced age, older patients (pts) are underrepresented in sarcoma clinical trials and evidence-based guidelines for chemotherapy are lacking. International oncological societies suggest using geriatric tools to evaluate older patients with cancer to optimise treatment indication. Comprehensive geriatric assessment (CGA) is a multidimensional assessment of older subjects, based on which pts can be classified as fit, vulnerable or frail. Onco-MPI (multidimensional prognostic index) is a CGA-based score which also considers tumour characteristics, classifying pts into three risk groups of death at one year: high-risk, intermediate-risk and low-risk. Methods: This is a single-centre retrospective study which aims at describing real-word management and outcomes of older pts with advanced stage STS and at assessing the ability of CGA and onco-MPI to predict survival in these pts. Consecutive pts with advanced stage STS aged 70 years or older and treated at the Istituto Oncologico Veneto from January 2009 to June 2020 were retrieved from a prospectively maintained database. Pts' demographics, CGA assessments and tumour characteristics were analysed. Statistical analysis was performed with R version 3.4.3 Results: Out of 101 pts, with a median age of 77 years, 76 received chemotherapy (75.3%), which was anthracycline-based for 46 pts (60.5%). Anthracyclines were used in a higher proportion in fit pts (58.9% fit vs. 45.1% vulnerable vs. 12.5% frail pts). Frail pts and pts in the onco-MPI high-risk group experienced a higher rate of chemotherapy-related toxicities. Median OS was 13.8 months (95% CI 11.3–17.7 months). According to CGA, the median OS was 19.53 months (95% CI 15.23–36.8) for fit pts, 12.83 months (95% CI 9.7–17.5) for vulnerable and 7.75 months (95% CI 2.73–30) for frail pts (p = 0.005). Onco-MPI confirmed a predictive value for 1-year survival with intermediate risk pts not reaching a median OS at 1 year, and high-risk pts having a median one-year OS of 11.5 months (95%CI 9.7–NA), p = 0.02. In multivariate analysis, onco-MPI and CGA were associated with survival (high risk onco-MPI: HR 5.5, 95%CI 1.25–24.7 p = 0.02; fitness at CGA HR 0.552 95% 0.314–0.973; p = 0.040) as well as chemotherapy use (HR 0.24, 95% CI 0.11–0.51, p < 0.005). Conclusions: Both CGA and onco-MPI retain prognostic value for survival in pts with metastatic STS. Pts frail/vulnerable at CGA and pts within the onco-MPI high risk category should be offered an oncogeriatric management approach in order to optimise treatment-related survival and reduce toxicity. [ABSTRACT FROM AUTHOR]

Simple Summary: Esophageal cancer is an aggressive disease with dismal survival. Circulating tumor cells (CTCs) may provide useful information for the unmet needs of early predictive and prognostic biomarkers for therapeutic responses and disease progression. Our novel longitudinal CTC findings demonstrated the potential clinical utilities of real-time CTC monitoring for locally advanced esophageal squamous cell carcinoma (ESCC) patients along with curative resection treatment at multiple timepoints for prediction of treatment efficacies, prognostication, and real-time tracking of minimal residual disease for earlier detection of relapse. The presence of pre-surgery CTC clusters is independently associated with relapse. The unfavorable CTC status at any pre-treatment time and 1-/3-month post-surgery are independent prognosticators of disease progression and survival. For patients receiving chemoradiation therapy (CTRT), unfavorable CTC status at pre-/post-CTRT may serve as potential predictive biomarkers for monitoring treatment efficacy and guiding treatment decisions. Longitudinal CTC monitoring may be taken repetitively as non-invasive liquid biopsies to provide supplementary information with clinical imaging. We aim to reveal the clinical significance and potential usefulness of dynamic monitoring of CTCs to track therapeutic responses and improve survival for advanced ESCC patients. Peripheral blood (PB) (n = 389) and azygos vein blood (AVB) (n = 13) samplings were recruited prospectively from 88 ESCC patients undergoing curative surgery from 2017 to 2022. Longitudinal CTC enumeration was performed with epithelial (EpCAM/pan-cytokeratins/MUC1) and mesenchymal (vimentin) markers at 12 serial timepoints at any of the pre-treatment, all of the post-treatments/pre-surgery, post-surgery follow-ups for 3-year, and relapse. Longitudinal real-time CTC analysis in PB and AVB suggests more CTCs are released early at pre-surgery and 3-month post-surgery into the circulation from the CTRT group compared to the up-front surgery group. High CTC levels at pre-treatments, 1-/3-month post-surgery, unfavorable changes of CTC levels between all post-treatment/pre-surgery and 1-month or 3-month post-surgery (Hazard Ratio (HR) = 6.662, p < 0.001), were independent prognosticators for curative treatment. The unfavorable pre-surgery CTC status was independent prognostic and predictive for neoadjuvant treatment efficacy (HR = 3.652, p = 0.035). The aggressive CTC clusters were more frequently observed in AVB compared to PB. Its role as an independent prognosticator with relapse was first reported in ESCC (HR = 2.539, p = 0.068). CTC clusters and longitudinal CTC monitoring provide useful prognostic information and potential predictive biomarkers to help guide clinicians in improving disease management. [ABSTRACT FROM AUTHOR]

Background: Merkel cell carcinoma (MCC) is a rare but highly aggressive neuroendocrine skin malignancy, with Australia having the highest reported incidence in the world. There is currently a lack of consensus regarding optimal management of this disease. Methods: This was a retrospective audit conducted by reviewing existing medical records of MCC patients presenting to the Peter MacCallum Cancer Centre (PMCC) between 1980 and 2018. The primary endpoint was locoregional recurrence. The secondary endpoints were distant recurrence, disease-free survival (DFS) and overall survival (OS). Results: A total of 533 patients were identified. Locoregional recurrence occurring at one, two and 5 years was 24, 31 and 32%, respectively. The estimated 5-year OS and DFS were 46% (95% Confidence Interval [CI] 41–51%) and 34% (95% CI 30–39%) respectively. Older age at diagnosis (hazard ratio [HR] per year = 1.07, 95% CI 1.06–1.07, p < 0.001), and larger primary tumour diameter (HR =1.16, 95% CI 1.03–1.31, p = 0.019) were associated with worse OS on multivariable analysis. Positive or negative histopathological margin status was not associated with OS or DFS differences in patients treated with post-operative radiotherapy. Conclusions: In our study, about a third of patients developed locoregional recurrence, distal recurrence or both, and there appears to be no change over the last four decades. If treated with adjuvant radiotherapy, there is no difference in OS or DFS with positive surgical margins. Findings should influence future guidelines. [ABSTRACT FROM AUTHOR]

Background: Merkel cell carcinoma (MCC) is a rare but highly aggressive neuroendocrine skin malignancy, with Australia having the highest reported incidence in the world. There is currently a lack of consensus regarding optimal management of this disease. Methods: This was a retrospective audit conducted by reviewing existing medical records of MCC patients presenting to the Peter MacCallum Cancer Centre (PMCC) between 1980 and 2018. The primary endpoint was locoregional recurrence. The secondary endpoints were distant recurrence, disease-free survival (DFS) and overall survival (OS). Results: A total of 533 patients were identified. Locoregional recurrence occurring at one, two and 5 years was 24, 31 and 32%, respectively. The estimated 5-year OS and DFS were 46% (95% Confidence Interval [CI] 41–51%) and 34% (95% CI 30–39%) respectively. Older age at diagnosis (hazard ratio [HR] per year = 1.07, 95% CI 1.06–1.07, p < 0.001), and larger primary tumour diameter (HR =1.16, 95% CI 1.03–1.31, p = 0.019) were associated with worse OS on multivariable analysis. Positive or negative histopathological margin status was not associated with OS or DFS differences in patients treated with post-operative radiotherapy. Conclusions: In our study, about a third of patients developed locoregional recurrence, distal recurrence or both, and there appears to be no change over the last four decades. If treated with adjuvant radiotherapy, there is no difference in OS or DFS with positive surgical margins. Findings should influence future guidelines. [ABSTRACT FROM AUTHOR]

Simple Summary: The emergence of atypical response (AR) has challenged the process of response evaluation and the subsequent management of non-small cell lung cancer (NSCLC) patients treated with PD-1/PD-L1 inhibitors. We conducted a multicenter retrospective analysis and found that AR was not an uncommon event in patients with metastatic NSCLC treated with the PD1/PD-L1 inhibitor. The median time to AR occurrence was 2.0 months, and patients with ≥3 metastatic organs at baseline were more likely to develop AR. For patients with AR, the common sites of progressive lesions were the lymph nodes and lungs. Furthermore, the majority of patients with AR had only 1–2 progressive tumor lesions, and most of the progressive lesions developed from originally existing tumor sites. Patients with AR had a comparable prognosis to those with a typical response (TR). Proper local therapy targeting progressive tumor lesions while maintaining the PD1/PD-L1 inhibitor may be a feasible treatment selection for patients with AR. Purpose: To explore the clinical characteristics, management, and survival outcomes of advanced NSCLC patients treated with PD-1/PD-L1 inhibitors who presented with an atypical response (AR). Methods: A total of 926 PD-1/PD-L1-inhibitor-treated patients with metastatic NSCLC from three academic centers were retrospectively reviewed. All measurable lesions were evaluated by RECIST version 1.1. Results: Fifty-six (6.1%) patients developed AR. The median time to the occurrence of AR was 2.0 months. Patients with no fewer than 3 metastatic organs at baseline were more prone to develop AR in advanced NSCLC (p = 0.038). The common sites of progressive lesions were lymph nodes (33.8%) and lungs (29.7%). The majority (78.2%) of patients with AR had only 1–2 progressive tumor lesions, and most (89.1%) of the progressive lesions developed from originally existing tumor sites. There was no significance in terms of survival between patients with AR and those with typical response (TR). Local therapy was an independent predictor for PFS of patients with AR (p = 0.025). Conclusions: AR was not an uncommon event in patients with metastatic NSCLC treated with PD-1/PD-L1 inhibitors, and it had a comparable prognosis to those with TR. Proper local therapy targeting progressive lesions without discontinuing original PD-1/PD-L1 inhibitors may improve patient survival. [ABSTRACT FROM AUTHOR]

The heterogeneity of hepatocellular carcinoma (HCC) is related to immune cell infiltration and genetic aberrations in the tumor microenvironment. This study aimed to identify the novel molecular typing of HCC according to the genetic and immune characteristics, to obtain accurate clinical management of this disease. We performed consensus clustering to divide 424 patients into different immune subgroups and assessed the reproducibility and efficiency in two independent cohorts with 921 patients. The associations between molecular typing and molecular, cellular, and clinical characteristics were investigated by a multidimensional bioinformatics approach. Furthermore, we conducted graph structure learning-based dimensionality reduction to depict the immune landscape to reveal the interrelation between the immune and gene systems in molecular typing. We revealed and validated that HCC patients could be segregated into 5 immune subgroups (IS1-5) and 7 gene modules with significantly different molecular, cellular, and clinical characteristics. IS5 had the worst prognosis and lowest enrichment of immune characteristics and was considered the immune cold type. IS4 had the longest overall survival, high immune activity, and antitumorigenesis, which were defined as the immune hot and antitumorigenesis types. In addition, immune landscape analysis further revealed significant intraclass heterogeneity within each IS, and each IS represented distinct clinical, cellular, and molecular characteristics. Our study provided 5 immune subgroups with distinct clinical, cellular, and molecular characteristics of HCC and may have clinical implications for precise therapeutic strategies and facilitate the investigation of immune mechanisms in HCC. [ABSTRACT FROM AUTHOR]

Background: Understanding risk factors for short- and long-term COVID-19 outcomes have implications for current guidelines and practice. We study whether early identified risk factors for COVID-19 persist one year later and through varying disease progression trajectories. Methods: This was a retrospective study of 6,731 COVID-19 patients presenting to Michigan Medicine between March 10, 2020 and March 10, 2021. We describe disease progression trajectories from diagnosis to potential hospital admission, discharge, readmission, or death. Outcomes pertained to all patients: rate of medical encounters, hospitalization-free survival, and overall survival, and hospitalized patients: discharge versus in-hospital death and readmission. Risk factors included patient age, sex, race, body mass index, and 29 comorbidity conditions. Results: Younger, non-Black patients utilized healthcare resources at higher rates, while older, male, and Black patients had higher rates of hospitalization and mortality. Diabetes with complications, coagulopathy, fluid and electrolyte disorders, and blood loss anemia were risk factors for these outcomes. Diabetes with complications, coagulopathy, fluid and electrolyte disorders, and blood loss were associated with lower discharge and higher inpatient mortality rates. Conclusions: This study found differences in healthcare utilization and adverse COVID-19 outcomes, as well as differing risk factors for short- and long-term outcomes throughout disease progression. These findings may inform providers in emergency departments or critical care settings of treatment priorities, empower healthcare stakeholders with effective disease management strategies, and aid health policy makers in optimizing allocations of medical resources. [ABSTRACT FROM AUTHOR]

Background: Cancer patients with brain metastases (BMs) require multidisciplinary care, and treatment facility may play a role. This study aimed to investigate the impact of receiving treatment at academic centers on the overall survival (OS) of cancer patients with brain metastases (BMs) regardless of the primary cancer site.Methods: This retrospective analysis of the National Cancer Database (NCDB) included patients diagnosed with non-small cell lung cancer, small-cell lung cancer, other types of lung cancer, breast cancer, melanoma, colorectal cancer, and kidney cancer and had brain metastases at the time of diagnosis. The data were extracted from the de-identified file of the NCDB, a joint program of the Commission on Cancer of the American College of Surgeons and the American Cancer Society. The Cox proportional hazard model adjusted for age at diagnosis, race, sex, place of living, income, education, primary tumor type, year of diagnosis, chemotherapy, radiation therapy (RT), and surgery of the primary cancer site was used to determine treatment facility-associated hazard ratios (HR) for survival. Overall survival was the primary outcome, which was analyzed with multivariable Cox proportional hazards regression modeling.Results: A total of 93,633 patients were analyzed, among whom 31,579/93,633 (34.09%) were treated at academic centers. Based on the log-rank analysis, patients who received treatment at an academic facility had significantly improved OS (median OS: 6.18, CI: 6.05-6.31 vs. 4.57, CI: 4.50-4.63 months; p < 0.001) compared to patients who were treated at non-academic facilities. In the multivariable Cox regression analysis, receiving treatment at an academic facility was associated with significantly improved OS (HR: 0.85, CI: 0.84-0.87; p < 0.001) compared to non-academic facility.Conclusions: In this extensive analysis of the NCDB, receiving treatment at academic centers was associated with significantly improved OS compared to treatment at non-academic centers. [ABSTRACT FROM AUTHOR]

Cervical cancer, a pernicious gynecological malignancy, causes the mortality of hundreds of thousands of females worldwide. Despite a considerable decline in mortality, the surging incidence rate among younger women has raised serious concerns. Immortality is the most important characteristic of tumor cells, hence the carcinogenesis of cervical cancer cells pivotally requires compromising with cell death mechanisms. The current study comprehensively reviewed the mechanisms of non-apoptotic cell death programs to provide possible disease management strategies. Comprehensive evidence has stated that focusing on necroptosis, pyroptosis, and autophagy for disease management is associated with significant limitations such as insufficient understanding, contradictory functions, dependence on disease stage, and complexity of intracellular pathways. However, ferroptosis represents a predictable role in cervix carcinogenesis, and ferroptosis-related genes demonstrate a remarkable correlation with patient survival and clinical outcomes. Ferroptosis may be an appropriate option for disease management strategies from predicting prognosis to treatment. [Display omitted] • The function of necroptosis, pyroptosis, and autophagy in cervical cancer is dual. • Depending on various factors, they may cause tumor suppression/progression. • The suppression of ferroptosis is one of the main provisions for tumor progression. • The steady role of ferroptosis in the disease makes it a desired therapeutic target. • Different expressions of ferroptosis-related genes could be prognosis predictors [ABSTRACT FROM AUTHOR]

Background: Peri-operative radiation of retroperitoneal sarcomas (RPS) is an important component of multidisciplinary treatment. All retrospective series thus far included patients treated with older radiation therapy (RT) techniques including 2D and 3DRT. Intensity modulated radiation therapy (IMRT) allows for selective dose escalation while sparing adjacent organs. We therefore report the first series of patients with RPS treated solely with IMRT, surgery and chemotherapy. We hypothesized that IMRT would permit safe dose escalation and superior rates of local control (LC) in this high-risk patient population.Methods: Thirty patients with RPS treated with curative intent between 2006 and 2015 were included in this retrospective study. RT was administered either pre- or post-operatively and IMRT was used in all patients. Statistical comparisons, LC, distant metastasis (DM), and overall survival (OS) were calculated by Kaplan-Meier analysis and univariate Cox regression.Results: Median follow-up time after completion of RT was 36 months (range 1.4-112). Median tumor size was 14 cm (range 3.6 - 28 cm). The most prevalent histologies were liposarcoma in 10 (33%) patients and leiomyosarcoma in 10 (33%) with 21 patients (70%) having high-grade disease. Twenty-eight (93%) patients had surgical resection with 47% having positive margins. Chemotherapy was administered in 9 (30%) patients. RT was delivered pre-operatively in 11 (37%) patients, and post-operatively in 19 (63%) with 60% of patients receiving a simultaneous integrated boost. Pre-operative median RT dose to the high-risk area was 55 Gy (range, 43-66 Gy) while median post-operative dose was 60.4 Gy (range, 45-66.6 Gy). There was one acute grade 3 and one late grade 3 toxicity and no grade 4 or 5 toxicities. Three year actuarial LC, freedom from DM, and OS rates were 84%, 64%, and 68% respectively. Positive surgical margins were associated with a higher risk of local recurrence (p = 0.02) and decreased OS (p = 0.04). Pre-operative RT was associated with improved LC (p = 0.1) with a 5-year actuarial LC of 100%. Administration of chemotherapy, timing of RT, histology or grade was not predictive of OS.Conclusions: Patients with RPS treated with peri-operative IMRT at our institution had excellent local control and low incidences of toxicity. [ABSTRACT FROM AUTHOR]

Background: Whether perioperative blood transfusions (PBTs) adversely influence oncological outcomes for intrahepatic cholangiocarcinoma (ICC) patients after curative resection remains undetermined.Methods: Of the 605 patients who underwent curative liver resection for ICC between 2000 and 2012, 93 received PBT. We conducted Cox regression and variable selection logistic regression analyses to identify confounding factors of PBT. Propensity score matching (PSM) and Cox regression analyses were used to compare the overall survival (OS) and disease-free survival (DFS) between the patients with or without PBT.Results: After exclusion, 93 eligible patients (15.4%) received PBT, compared with 512 (84.6%) who did not receive PBT; the groups were highly biased in terms of the propensity score (PS) analysis (0.096 ± 0.104 vs. 0.479 ± 0.372, p < 0.001). PBT was associated with an increased risk of OS (HR: 1.889, 95% CI: 1.446-2.468, p < 0.001) and DFS (HR: 1.589, 95% CI: 1.221-2.067, p < 0.001) in the entire cohort. After propensity score matching (PSM), no bias was observed between the groups (PS,0.136 ± 0.117 VS. 0.193 ± 0.167, p = 0.785). In the multivariate Cox analysis, PBT was not associated with increased risks of OS (HR: 1.172, 95% CI: 0.756-1.816, p = 0.479) and DFS (HR: 0.944, 95% CI: 0.608-1.466, p = 0.799). After propensity score adjustment, PBT was still not associated with OS or DFS after ICC curative resection.Conclusions: The present study found that PBT did not affect DFS and OS after curative resection of ICC. [ABSTRACT FROM AUTHOR]