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Purpose: To identify the predictors and outcomes of ICU triage decisions in patients with solid malignancies (SM) and to investigate the usefulness of the National Early Warning Score (NEWS) and quick Sequential Organ Failure Assessment (qSOFA) score at triage., Methods: All patients with SM for whom ICU admission was requested between July 2019 and December 2021 in a French university-affiliated hospital were included prospectively., Results: Of the 6262 patients considered for ICU admission, 410 (6.5%) had SM (age, 66 [58-73] years; metastases, 60.1%; and performance status 0-2, 81%). Of these 410 patients, 176 (42.9%) were admitted to the ICU, including 141 (80.1%) subsequently discharged alive. Breast cancer, hemoptysis, and pneumothorax were associated with ICU admission; whereas older age, performance status 3-4, metastatic disease, and request at night were associated with denial of ICU admission. The NEWS, and the qSOFA score in patients with suspected infection, determined at triage performed poorly for predicting hospital mortality (area under the receiver operating characteristics curve, 0.52 and 0.62, respectively). Performance status 3-4 was independently associated with higher 6-month mortality and first-line anticancer treatment with lower 6-month mortality. Hospital mortality was 33.3% in patients admitted to the ICU after refusal of the first request., Conclusion: Patients with SM were frequently denied ICU admission despite excellent in-ICU survival. Poor performance status was associated with ICU admission denial and higher 6-month mortality, but none of the other reasons for denying ICU admission predicted 6-month mortality. Physiological scores had limited usefulness in this setting., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The study aimed to describe the epidemiology of multidrug-resistant (MDR) bacteria among solid cancer (SC) patients with bloodstream infections (BSIs), evaluating inappropriate empiric antibiotic treatment (IEAT) use and mortality trends over a 25-year period. All BSI occurrences in adult SC patients at a university hospital were analyzed across five distinct five-year intervals. MDR bacteria were classified as extended-spectrum beta-lactamases (ESBL)-producing and/or Carbapenem-resistant Enterobacterales, non-fermenting Gram-negative bacilli (GNB) resistant to at least three antibiotic classes, methicillin-resistant Staphylococcus aureus (MRSA), and Vancomycin-resistant Enterococci . A multivariate regression model identified the risk factors for MDR BSI. Of 6,117 BSI episodes, Gram-negative bacilli (GNB) constituted 60.4% (3,695/6,117), being the most common are Escherichia coli with 26.8% (1,637/6,117), Klebsiella spp. with 12.4% (760/6,117), and Pseudomonas aeruginosa with 8.6% (525/6,117). MDR-GNB accounted for 644 episodes (84.8% of MDR or 644/759), predominantly ESBL-producing strains (71.1% or 540/759), which escalated significantly over time. IEAT was administered in 24.8% of episodes, mainly in MDR BSI, and was associated with higher mortality (22.9% vs. 14%, P < 0.001). Independent factors for MDR BSI were prior antibiotic use [odds ratio (OR) 2.93, confidence interval (CI) 2.34-3.67], BSI during antibiotic treatment (OR 1.46, CI 1.18-1.81), biliary (OR 1.84, CI 1.34-2.52) or urinary source (OR 1.86, CI 1.43-2.43), admission period (OR) 1.28, CI 1.18-1.38, and community-acquired infection (OR 0.57, CI 0.39-0.82). The study showed an increase in MDR-GNB among SC patients with BSI. A quarter received IEAT, which was linked to increased mortality. Improving risk assessment for MDR infections and the judicious prescription of empiric antibiotics are crucial for better outcomes., Importance: Multidrug-resistant (MDR) bacteria pose a global public health threat as they are more challenging to treat, and they are on the rise. Solid cancer patients are often immunocompromised due to their disease and cancer treatments, making them more susceptible to infections. Understanding the changes and trends in bloodstream infections in solid cancer patients is crucial, to help physicians make informed decisions about appropriate antibiotic therapies, manage infections in this vulnerable population, and prevent infection. Solid cancer patients often require intensive and prolonged treatments, including surgery, chemotherapy, and radiation therapy. Infections can complicate these treatments, leading to treatment delays, increased healthcare costs, and poorer patient outcomes. Investigating new strategies to combat MDR infections and researching novel antibiotics in these patients is of paramount importance to avoid these negative impacts., Competing Interests: C.G.-V. has received honoraria for talks on behalf of Gilead Sciences, MSD, Novartis, Pfizer, Janssen, and Lilly, as well as a grant from Gilead Sciences, Pfizer, and MSD. P.P.-A. has received honoraria for talks on behalf of Merck Sharp & Dohme, Gilead, Lilly, ViiV Healthcare, and Gilead Sciences. A.S. has received honoraria for talks on behalf of Merck Sharp & Dohme, Pfizer, Novartis, Angelini, Menarini, and Gilead Sciences, as well as grant support from Pfizer and Gilead Sciences. O.P. has received honoraria for talks on behalf of MSD, Qiagen, and expertise for Sanofi.

Background: Many cancer patients experience malnutrition, which can worsen their health and survival outcomes. However, limited research exists in our region on how common malnutrition is among hospitalized adults with solid tumors and what factors contribute to it. This study aimed to identify these factors and assess the effects of nutritional impact symptoms (NISs) caused by solid tumors on patients' nutritional status., Methods: Between July 2022 and February 2023, a cross-sectional study was carried out on the campuses of two major cancer treatment centers located in a national university hospital and a governmental hospital. Twelve NISs were adopted from the Patient-Generated Subjective Global Assessments (PG-SGA). The Nutrition Risk Screening 2002 (NRS-2002) instrument was used to thoroughly assess the risk of malnutrition. Multiple linear regressions were used to conduct a thorough study., Results: A cohort of 294 participants was included. The prevalence of malnutrition risk (NRS score ≥ 3) was 26.9%. Parameters such as age, gender, marital status, educational level, monthly income, type of cancer and treatment modality, and the need for mealtime assistance exhibited statistically significant associations with malnutrition (p < 0.05). The results revealed a substantial inverse correlation between fluid intake and the NRS-2002 score (p < 0.001). Furthermore, symptoms related to solid tumors and their treatment, including chewing difficulties, fatigue, dry mouth, anorexia, constipation, nausea, dizziness, and a sensation of fullness, were also significantly associated with malnutrition (p < 0.05). Additional insights from the regression analysis underscored the independent correlation between the risk of malnutrition in solid malignant malignancies and factors such as anorexia (p < 0.001), colorectal cancer (p = 0.003), gender (p = 0.018), educational attainment (p = 0.049), and the need for mealtime assistance among patients (p < 0.001)., Conclusions: Malnutrition is a major issue among adult cancer patients, particularly those with solid tumors. Anorexia, colorectal cancer, gender, educational attainment, and the need for mealtime assistance were identified as factors that led to malnutrition in our research. This study emphasizes the need for a multidisciplinary plan of care to diagnose and treat malnutrition, improve overall therapy, and reduce mortality and morbidity., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Peritumoral fibrosis is known to promote cancer progression and confer treatment resistance in various solid tumors. Consequently, developing accurate cancer research and drug screening models that replicate the structure and function of a fibrosis-surrounded tumor mass is imperative. Previous studies have shown that self-assembly three-dimensional (3D) co-cultures primarily produce cancer-encapsulated fibrosis or maintain a fibrosis-encapsulated tumor mass for a short period, which is inadequate to replicate the function of fibrosis, particularly as a physical barrier. To address this limitation, a multi-layer spheroid formation method is developed to create a fibrosis-encapsulated tumoroid (FET) structure that maintains structural stability for up to 14 days. FETs exhibited faster tumor growth, higher expression of immunosuppressive cytokines, and equal or greater resistance to anticancer drugs compared to their parental tumoroids. Additionally, FETs serve as a versatile model for traditional cancer research, enabling the study of exosomal miRNA and gene functions, as well as for mechanobiology research when combined with alginate hydrogel. Our findings suggest that the FET represents an advanced model that more accurately mimics solid cancer tissue with peritumoral fibrosis. It may show potential superiority over self-assembly-based 3D co-cultures for cancer research and drug screening, and holds promise for personalized drug selection in cancer treatment., (© 2024 The Author(s). Advanced Healthcare Materials published by Wiley‐VCH GmbH.)

Solid cancer patients, compared to their healthy counterparts, are at a greater risk of contracting and suffering from severe complications and poorer prognosis after COVID-19 infections. They also have different immune responses after doses of COVID-19 vaccination, but limited evidence is available to reveal the effectiveness and help to guide immunization programs for this subpopulation; MEDLINE, Embase, Web of Science, Cochrane Library databases, and clinicaltrials.gov were used to search literature. The pooled seroconversion rate was calculated using a random-effects model and reported with a 95% confidence interval (CI); The review includes 66 studies containing serological responses after COVID-19 vaccination in 13,050 solid cancer patients and 8550 healthy controls. The pooled seropositive rates after the first dose in patients with solid cancer and healthy controls are 55.2% (95% CI 45.9%-64.5% N  = 18) and 90.2% (95% CI 80.9%-96.6% N  = 13), respectively. The seropositive rates after the second dose in patients with solid cancer and healthy controls are 87.6% (95% CI 84.1%-90.7% N  = 50) and 98.9% (95% CI 97.6%-99.7% N  = 35), respectively. The seropositive rates after the third dose in patients with solid cancer and healthy controls are 91.4% (95% CI 85.4%-95.9% N  = 21) and 99.8% (95% CI 98.1%-100.0% N  = 4), respectively. Subgroup analysis finds that study sample size, timing of antibody testing, and vaccine type have influence on the results; Seroconversion rates after COVID-19 vaccination are significantly lower in patients with solid malignancies, especially after the first dose, then shrinking gradually after the following two vaccinations, indicating that subsequent doses or a booster dose should be considered for the effectiveness of this subpopulation.

Improving short- and long-term outcomes in immunosuppressed patients, including patients with cancer, solid-organ transplant recipients, and patients with short- and long-term steroid treatment, has led to a paradigm shift in intensive care unit admission policies. Approximately 20% of patients currently admitted to the ICU carry a diagnosis of immune deficiency. In this population, acute respiratory failure and acute respiratory distress syndrome are the most frequent causes of ICU admission. Intensivists should therefore be aware of etiologies, diagnostics, and management strategies unique to this population., Competing Interests: Disclosure N. Buchtele and L. Munshi declare no conflict of interest., (Crown Copyright © 2024. Published by Elsevier Inc. All rights reserved.)

Background: We examined the treatment outcomes following intramedullary nailing in patients with metastatic femoral tumors, excluding those from hematological malignancies., Methods: We retrospectively evaluated treatment outcomes following intramedullary nailing between patients who underwent preventative surgery compared with those who had surgery following pathological fracture. Patients who underwent preventative surgery (Mirels' score ≥8) were allocated to the impending fracture group (n = 11) and those who underwent surgery after pathological fracture were allocated to the completed fracture group (n = 20)., Results: Duration of surgery was significantly shorter in the impending fracture group than in the completed fracture group. Median blood loss was significantly less, and the median duration of hospital stay was significantly shorter in the impending fracture group than in the completed fracture group. Among patients who died following surgery, the median postoperative survival duration was significantly longer in the impending fracture group than in the completed fracture group. Significantly more patients regained walking function in the impending fracture group than in the completed fracture group. Regarding complications, infection occurred in one patient in the completed fracture group. No implant damage was observed in either group., Conclusions: Patients with metastatic femoral tumors who underwent intramedullary nailing in the impending fracture group had better postoperative survival and gait function, less blood loss, and shorter durations of surgery and hospital stay than those in the completed fracture group. These findings indicate the importance of early diagnosis and treatment and value of treatment prior to fracture occurrence., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest., (Copyright © 2023 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

In recent years, next-generation sequencing (NGS)-based genetic testing has become crucial in cancer care. While its primary objective is to identify actionable genetic alterations to guide treatment decisions, its scope has broadened to encompass aiding in pathological diagnosis and exploring resistance mechanisms. With the ongoing expansion in NGS application and reliance, a compelling necessity arises for expert consensus on its application in solid cancers. To address this demand, the forthcoming recommendations not only provide pragmatic guidance for the clinical use of NGS but also systematically classify actionable genes based on specific cancer types. Additionally, these recommendations will incorporate expert perspectives on crucial biomarkers, ensuring informed decisions regarding circulating tumor DNA panel testing.

Purpose: This study investigated the incidence of secondary malignancy in multiple myeloma (MM) patients compared with that in the general population using a population-based database covering all residents in Korea., Materials and Methods: Based on the national health insurance system in Korea, all people primarily diagnosed with MM between January 1, 2010 to December 31, 2018 were identified. A total of 9,985 MM patients aged ≥ 20 years in Korea were included., Results: Among them, 237 (2.4%) developed secondary malignancies by 2018. The standardized incidence rates (SIRs) of all secondary malignancies in MM patients were 0.87 (95% confidence interval [CI], 0.76 to 0.98), with a higher incidence of hematologic malignancies than in the general population with an SIR of 3.80 (95% CI, 2.61 to 5.00). The incidence rates of both lymphoid malignancy (SIR, 3.56; 95% CI, 2.31 to 4.82) and myeloid malignancy (SIR, 3.78; 95% CI, 1.16 to 6.39) were higher in MM patients than in the general population. In contrast, a lower incidence of solid cancer was observed in MM patients than in the general population (SIR, 0.76, 95% CI, 0.65 to 0.86). There was no significant difference in survival in MM patients without secondary malignancies, with hematologic malignancy, and with solid cancer (p=0.413)., Conclusion: MM patients had a greater risk of secondary malignancies, especially hematologic malignancies, than the general population. Future studies with a focus on analyzing patients' history, treatment details, and genetic information in various stages of MM patients are needed to better understand the mechanism behind this increased risk.

In recent years, next-generation sequencing (NGS)-based genetic testing has become crucial in cancer care. While its primary objective is to identify actionable genetic alterations to guide treatment decisions, its scope has broadened to encompass aiding in pathological diagnosis and exploring resistance mechanisms. With the ongoing expansion in NGS application and reliance, a compelling necessity arises for expert consensus on its application in solid cancers. To address this demand, the forthcoming recommendations not only provide pragmatic guidance for the clinical use of NGS but also systematically classify actionable genes based on specific cancer types. Additionally, these recommendations will incorporate expert perspectives on crucial biomarkers, ensuring informed decisions regarding circulating tumor DNA panel testing.

Numerous antibody biomarkers have been reported for cancer and atherosclerosis-related diseases. The major complications of atherosclerosis and diabetes mellitus (DM) are acute ischemic stroke (AIS), cardiovascular disease (CVD) and chronic kidney disease (CKD). Cancer development is accompanied by arterial disorders, such as angiogenesis and atherosclerosis, and DM is a risk factor for the development of certain types of cancer. Atherosclerosis-related diseases and cancers are therefore interrelated and could be detected using a common biomarker. In the present study, the initial screening using the protein array method identified KIAA0513 as an antigen recognized by serum IgG antibodies in patients with atherosclerosis. The amplified luminescent proximity homogeneous assay-linked immunosorbent assay revealed significantly higher serum antibody levels against recombinant KIAA0513 protein in patients with AIS, transient ischemic attack (TIA), DM, CVD, obstructive sleep apnea syndrome (OSAS), CKD and solid cancers, such as esophageal, gastric, colon, lung and breast cancers, compared with healthy donors. A receiver operating characteristic (ROC) analysis revealed that the highest areas under the ROC curves of anti-KIAA0513 antibodies were obtained for esophageal cancer, nephrosclerosis-type CKD and DM. Spearman's correlation analysis revealed that serum anti-KIAA0513 antibody levels were associated with maximum intima-media thickness and plaque score, which are indices of atherosclerosis and stenosis. Serum anti-KIAA0513 antibody markers appear to be useful for diagnosing AIS, TIA, DM, CVD, OSAS, CKD and solid cancers, and may reflect common arterial alterations leading to atherosclerotic and cancerous diseases., Competing Interests: The present study was performed in collaboration with Fujikura Kasei Co., Ltd. GT is an employee of Fujikura Kasei Co., Ltd. The other authors have no competing interests., (Copyright: © 2024 Hiwasa et al.)

Chimeric antigen receptor natural killer (CAR-NK) cell therapy represents a potent approach to suppressing tumor growth because it has simultaneously inherited the specificity of CAR and the intrinsic generality of NK cells in recognizing cancer cells. However, its therapeutic potency against solid tumors is still restricted by insufficient tumor infiltration, immunosuppressive tumor microenvironments, and many other biological barriers. Motivated by the high potency of puerarin, a traditional Chinese medicine extract, in dilating tumor blood vessels, an injectable puerarin depot based on a hydrogen peroxide-responsive hydrogel comprising poly(ethylene glycol) dimethacrylate and ferrous chloride is concisely developed. Upon intratumoral fixation, the as-prepared puerarin depot (abbreviated as puerarin@PEGel) can activate nitrogen oxide production inside endothelial cells and thus dilate tumor blood vessels to relieve tumor hypoxia and reverse tumor immunosuppression. Such treatment can thus promote tumor infiltration, survival, and effector functions of customized epidermal growth factor receptor (HER1)-targeted HER1-CAR-NK cells after intravenous administration. Consequently, such puerarin@PEGel-assisted HER1-CAR-NK cell treatment exhibits superior tumor suppression efficacy toward both HER1-overexpressing MDA-MB-468 and NCI-H23 human tumor xenografts in mice without inducing obvious side effects. This study highlights a potent strategy to activate CAR-NK cells for augmented treatment of targeted solid tumors through reprogramming tumor immunosuppression., (© 2024 Wiley‐VCH GmbH.)

Purpose: This systematic review and meta-analysis aimed to investigate the effectiveness of carbon ion radiotherapy (CIRT) compared to that of conventional radiotherapy in patients with various types of solid tumors., Materials and Methods: We systematically searched eight electronic databases from inception until August 2022 in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines. The comparative effectiveness of the different treatment options was assessed by a random-effects meta-analysis., Results: This review included 34 comparative studies and three treatment groups. Overall, the meta-analysis indicated comparable local control rates between the CIRT and control groups [pooled risk ratio (RR)=1.02, 95% confidence interval (CI) 0.90-1.15]. The local control rate in the CIRT group was higher than that in the photon therapy group, but slightly lower than that in the proton radiation therpy (PRT) group. Additionally, the CIRT group had significantly higher overall survival (OS) (RR=1.19, 95% CI=1.01-1.42) and progression-free survival (PFS) (RR=1.50, 95% CI=1.01-2.21) rates compared to the control group. In the subgroup analysis, survival rates were similar between the CIRT and PRT groups., Conclusion: CIRT was associated with improved toxicity, local tumor control, OS, and PFS compared to conventional treatments. Therefore, CIRT was found to be a safe and effective option for achieving local control in patients with solid tumors., Competing Interests: The authors have no potential conflicts of interest to disclose., (© Copyright: Yonsei University College of Medicine 2024.)

Introduction: Solid cancers Myeloid cells are prevalent in solid cancers, but they frequently exhibit an anti-inflammatory pro-tumor phenotype that contribute to the immunosuppressive tumor microenvironment (TME), which hinders the effectiveness of cancer immunotherapies. Myeloid cells' natural ability of tumor trafficking makes engineered myeloid cell therapy an intriguing approach to tackle the challenges posed by solid cancers, including tumor infiltration, tumor cell heterogenicity and the immunosuppressive TME. One such engineering approach is to target the checkpoint molecule PD-L1, which is often upregulated by solid cancers to evade immune responses., Method: Here we devised an adoptive cell therapy strategy based on myeloid cells expressing a Chimeric Antigen Receptor (CAR)-like immune receptor (CARIR). The extracellular domain of CARIR is derived from the natural inhibitory receptor PD-1, while the intracellular domain(s) are derived from CD40 and/or CD3ζ. To assess the efficacy of CARIR-engineered myeloid cells, we conducted proof-of-principle experiments using co-culture and flow cytometry-based phagocytosis assays in vitro. Additionally, we employed a fully immune-competent syngeneic tumor mouse model to evaluate the strategy's effectiveness in vivo., Result: Co-culturing CARIR-expressing human monocytic THP-1 cells with PD-L1 expressing target cells lead to upregulation of the costimulatory molecule CD86 along with expression of proinflammatory cytokines TNF-1α and IL-1β. Moreover, CARIR expression significantly enhanced phagocytosis of multiple PD-L1 expressing cancer cell lines in vitro. Similar outcomes were observed with CARIR-expressing human primary macrophages. In experiments conducted in syngeneic BALB/c mice bearing 4T1 mammary tumors, infusing murine myeloid cells that express a murine version of CARIR significantly slowed tumor growth and prolonged survival., Conclusion: Taken together, these results demonstrate that adoptive transfer of PD-1 CARIR-engineered myeloid cells represents a promising strategy for treating PD-L1 positive solid cancers., Competing Interests: Authors KC, DG, BG, SV, MM, A-HZ, and PA are employees and/or shareholders of Vita Therapeutics, Inc. A-HZ, PA, KC, and DG are inventors of pending patents involving the generation and use of CARIR-modified myeloid cells for treating cancer., (Copyright © 2024 Myers Chen, Grun, Gautier, Venkatesha, Maddox, Zhang and Andersen.)

Background: Nutritional impact symptoms (NISs) are proposed to be a key indicator of decreased dietary intake in patients with solid cancer. Cancer patients frequently experience NIS from the disease itself and from disease treatment side effects that impact oral and gastrointestinal health. Thus, this study aimed to investigate the association between NIS and dietary intake among cancer patients in the Nablus district, one of the largest districts in Palestine. This study also sought to identify the types of treatment and other factors related to dietary intake for solid cancer patients., Methods: A cross-sectional study was conducted between October 15, 2021, and October 15, 2022. The convenience sampling technique was used to recruit participants from two primary hospital campuses for cancer treatment in the entire region of Nablus Governorate in northern Palestine. To assess the patients, structured questionnaires completed by interviewers during face-to-face interviews with patients were used. The NIS was assessed using a checklist developed based on a literature review and clinical experience. Univariate and multivariate analyses were used to evaluate the correlations between sociodemographic variables and clinical variables and between the NIS and dietary intake. Multiple binary logistic regression analyses were also performed to determine the most influential variables, sociodemographic, clinical, and NIS, on dietary intake., Results: Data were collected from 290 patients with solid malignancies. The mean age of the participants was 55.04 ± 12.76 years. Multiple binary logistic regressions revealed that dry mouth (odds ratio (OR) = 3.742; 95% confidence interval (CI) = 1.800-7.780; p < 0.001), constipation (OR = 2.707; 95% CI = 1.113-6.581; p = 0.028), taste alteration (OR = 3.620; 95% CI = 1.752-7.481; p = 0.001), and feeling fullness (OR = 8.879; 95% CI = 2.982-26.441; p < 0.001) were significantly related to decreased dietary intake. Biological and hormonal treatments had an inverse association with dietary intake (OR = 0.372; 95% CI = 0.177-0.782; p = 0.009 and OR = 0.383; 95% CI = 0.168-0.874; p = 0.023, respectively)., Conclusions: This study revealed that many solid cancer patients have reduced food intake due to NIS, such as dry mouth and taste changes. These patients may be at risk of malnutrition. Healthcare professionals should consider these NISs to improve dietary plans and decide whether extra feeding support is needed. The results obtained indicate the need for further research focused on removing limitations in food consumption as an effect of treatment and appropriate nutritional strategies to prevent patient malnutrition., (© 2024. The Author(s).)

Background: Blocking the CD47 "don't eat me"-signal on tumor cells with monoclonal antibodies or fusion proteins has shown limited clinical activity in hematologic malignancies and solid tumors thus far. Main side effects are associated with non-tumor targeted binding to CD47 particularly on blood cells., Methods: We present here the generation and preclinical development of NILK-2401, a CEACAM5×CD47 bispecific antibody (BsAb) composed of a common heavy chain and two different light chains, one kappa and one lambda, determining specificity (so-called κλ body format)., Results: NILK-2401 is a fully human BsAb binding the CEACAM5 N-terminal domain on tumor cells by its lambda light chain arm with an affinity of ≈4 nM and CD47 with its kappa chain arm with an intendedly low affinity of ≈500 nM to enabling tumor-specific blockade of the CD47-SIRPα interaction. For increased activity, NILK-2401 features a functional IgG1 Fc-part. NILK-2401 eliminates CEACAM5-positive tumor cell lines (3/3 colorectal, 2/2 gastric, 2/2 lung) with EC 50 for antibody-dependent cellular phagocytosis and antibody-dependent cellular cytotoxicity ranging from 0.38 to 25.84 nM and 0.04 to 0.25 nM, respectively. NILK-2401 binds neither CD47-positive/CEACAM5-negative cell lines nor primary epithelial cells. No erythrophagocytosis or platelet activation is observed. Quantification of the pre-existing NILK-2401-reactive T-cell repertoire in the blood of 14 healthy donors with diverse HLA molecules shows a low immunogenic potential. In vivo , NILK-2401 significantly delayed tumor growth in a NOD-SCID colon cancer model and a syngeneic mouse model using human CD47/human SIRPα transgenic mice and prolonged survival. In cynomolgus monkeys, single doses of 0.5 and 20 mg/kg were well tolerated; PK linked to anti-CD47 and Fc-binding seemed to be more than dose-proportional for C max and AUC 0-inf . Data were validated in human FcRn TG32 mice. Combination of a CEACAM5-targeting T-cell engager (NILK-2301) with NILK-2401 can either boost NILK-2301 activity (Emax) up to 2.5-fold or allows reaching equal NILK-2301 activity at >600-fold (LS174T) to >3,000-fold (MKN-45) lower doses., Conclusion: NILK-2401 combines promising preclinical activity with limited potential side effects due to the tumor-targeted blockade of CD47 and low immunogenicity and is planned to enter clinical testing., Competing Interests: AS and DH declare employment at LamKap Bio Group. VB, VM, BD, FR, LC, AV, NB, ER, KM, CB, CM, FJ-B, and YP declare employment at Light Chain Bioscience - Novimmune SA. SS-P declares consultancy work for Light Chain Bioscience - Novimmune SA and LamKap Bio. The authors declare that this study received funding from LamKap Bio beta. The funder or its employees had the following involvement in the study: study design, data analysis, decision to publish, and preparation of the manuscript. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Seckinger, Buatois, Moine, Daubeuf, Richard, Chatel, Viandier, Bosson, Rousset, Masternak, Salgado-Pires, Batista, Mougin, Juan-Bégeot, Poitevin and Hose.)

Immune checkpoint inhibitors (ICI) and tyrosine kinase inhibitors (TKI) have gained therapeutical significance in cancer therapy over the last years. Due to the high efficacy of each substance group, additive or complementary effects are considered, and combinations are the subject of multiple prospective trials in different tumor entities. The majority of available data results from clinical phase I and II trials. Although regarded as well-tolerated therapies ICI-TKI combinations have higher toxicities compared to monotherapies of one of the substance classes and some combinations were shown to be excessively toxic leading to discontinuation of trials. So far, ICI-TKI combinations with nivolumab + cabozantinib, pembrolizumab + axitinib, avelumab + axitinib, pembrolizumab + lenvatinib have been approved in advanced renal cell (RCC), with pembrolizumab + lenvatinib in endometrial carcinoma and with camrelizumab + rivoceranib in hepatocellular carcinoma (HCC). Several ICI-TKI combinations are currently investigated in phase I to III trials in various other cancer entities. Further, the optimal sequence of ICI-TKI combinations is an important subject of investigation, as cross-resistances between the substance classes were observed. This review reports on clinical trials with ICI-TKI combinations in different cancer entities, their efficacy and toxicity., Competing Interests: Declaration of competing interest AMS received travel and congress registration support from MSD, Lilly and PharmaMar and lecture honoraria from AstraZeneca. BK received honoraria for lectures or advisory board participation from AstraZeneca, Boehringer Ingelheim, BMS, Daiichi Sankyo, Eli Lilly, Ipsen, MSD, Novartis, Roche. AS received travel support from Lilly. JMR received travel support by Roche, Bristol-Meyers Squibb and lecture honoraria by Bristol-Meyers Squibb, Roche, Amgen and Novartis. MP has received honoraria for lectures, consultation or advisory board participation from the following for-profit companies: Bayer, Bristol-Myers Squibb, Novartis, Gerson Lehrman Group (GLG), CMC Contrast, GlaxoSmithKline, Mundipharma, Roche, BMJ Journals, MedMedia, Astra Zeneca, AbbVie, Lilly, Medahead, Daiichi Sankyo, Sanofi, Merck Sharp & Dome, Tocagen, Adastra, Gan & Lee Pharmaceuticals, Janssen, Servier, Miltenyi, Böhringer-Ingelheim, Telix, Medscape., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

PIM3 (provirus-integrating Moloney site 3) is a serine/threonine kinase and belongs to the PIM family (PIM1, PIM2, and PIM3). PIM3 is a proto-oncogene that is frequently overexpressed in cancers originating from endoderm-derived tissues, such as the liver, pancreas, colon, stomach, prostate, and breast cancer. PIM3 plays a critical role in activating multiple oncogenic signaling pathways promoting cancer cell proliferation, survival, invasion, tumor growth, metastasis, and progression, as well as chemo- and radiation therapy resistance and immunosuppressive microenvironment. Genetic inhibition of PIM3 expression suppresses in vitro cell proliferation and in vivo tumor growth and metastasis in mice with solid cancers, indicating that PIM3 is a potential therapeutic target. Although several pan-PIM inhibitors entered phase I clinical trials in hematological cancers, there are currently no FDA-approved inhibitors for the treatment of patients. This review provides an overview of recent developments and insights into the role of PIM3 in various cancers and its potential as a novel molecular target for cancer therapy. We also discuss the current status of PIM-targeted therapies in clinical trials.

The immune system, a central player in maintaining homeostasis, emerges as a pivotal factor in the pathogenesis and progression of two seemingly disparate yet interconnected categories of diseases: autoimmunity and cancer. This chapter delves into the intricate and multifaceted role of the immune system, particularly T cells, in orchestrating responses that govern the delicate balance between immune surveillance and self-tolerance. T cells, pivotal immune system components, play a central role in both diseases. In autoimmunity, aberrant T cell activation drives damaging immune responses against normal tissues, while in cancer, T cells exhibit suppressed responses, allowing the growth of malignant tumors. Immune checkpoint receptors, example, initially explored in autoimmunity, now revolutionize cancer treatment via immune checkpoint blockade (ICB). Though effective in various tumors, ICB poses risks of immune-related adverse events (irAEs) akin to autoimmunity. This chapter underscores the importance of understanding tumor-associated antigens and their role in autoimmunity, immune checkpoint regulation, and their implications for both diseases. It also explores autoimmunity resulting from cancer immunotherapy and shared molecular pathways in solid tumors and autoimmune diseases, highlighting their interconnectedness at the molecular level. Additionally, it sheds light on common pathways and epigenetic features shared by autoimmunity and cancer, and the potential of repurposing drugs for therapeutic interventions. Delving deeper into these insights could unlock therapeutic strategies for both autoimmunity and cancer., (Copyright © 2024. Published by Elsevier Inc.)

Therapeutic approaches for cancer have become increasingly diverse in recent times. A comprehensive understanding of the tumor microenvironment (TME) holds great potential for enhancing the precision of tumor therapies. Neoadjuvant therapy offers the possibility of alleviating patient symptoms and improving overall quality of life. Additionally, it may facilitate the reduction of inoperable tumors and prevent potential preoperative micrometastases. Within the TME, cancer-associated fibroblasts (CAFs) play a prominent role as they generate various elements that contribute to tumor progression. Particularly, extracellular matrix (ECM) produced by CAFs prevents immune cell infiltration into the TME, hampers drug penetration, and diminishes therapeutic efficacy. Therefore, this review provides a summary of the heterogeneity and interactions of CAFs within the TME, with a specific focus on the influence of neoadjuvant therapy on the microenvironment, particularly CAFs. Finally, we propose several potential and promising therapeutic strategies targeting CAFs, which may efficiently eliminate CAFs to decrease stroma density and impair their functions., Competing Interests: Declaration of Competing Interest There are no conflicts of interest to report from these authors., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: T-cell retargeting to eliminate CEACAM5-expressing cancer cells via CEACAM5xCD3 bispecific antibodies (BsAbs) showed limited clinical activity so far, mostly due to insufficient T-cell activation, dose-limiting toxicities, and formation of anti-drug antibodies (ADA)., Methods: We present here the generation and preclinical development of NILK-2301, a BsAb composed of a common heavy chain and two different light chains, one kappa and one lambda, determining specificity (so-called κλ body format)., Results: NILK-2301 binds CD3ɛ on T-cells with its lambda light chain arm with an affinity of ≈100 nM, and the CEACAM5 A2 domain on tumor cells by its kappa light chain arm with an affinity of ≈5 nM. FcγR-binding is abrogated by the "LALAPA" mutation (Leu234Ala, Leu235Ala, Pro329Ala). NILK-2301 induced T-cell activation, proliferation, cytokine release, and T-cell dependent cellular cytotoxicity of CEACAM5-positive tumor cell lines (5/5 colorectal, 2/2 gastric, 2/2 lung), e.g., SK-CO-1 (E max  = 89%), MKN-45 (E max  = 84%), and H2122 (E max  = 97%), with EC 50 ranging from 0.02 to 0.14 nM. NILK-2301 binds neither to CEACAM5-negative or primary colon epithelial cells nor to other CEACAM family members. NILK-2301 alone or in combination with checkpoint inhibition showed activity in organotypic tumor tissue slices and colorectal cancer organoid models. In vivo, NILK-2301 at 10 mg/kg significantly delayed tumor progression in colon- and a pancreatic adenocarcinoma model. Single-dose pharmacokinetics (PK) and tolerability in cynomolgus monkeys at 0.5 or 10 mg/kg intravenously or 20 mg subcutaneously showed dose-proportional PK, bioavailability ≈100%, and a projected half-life in humans of 13.1 days. NILK-2301 was well-tolerated. Data were confirmed in human FcRn TG32 mice., Conclusions: In summary, NILK-2301 combines promising preclinical activity and safety with lower probability of ADA-generation due to its format compared to other molecules and is scheduled to enter clinical testing at the end of 2023., (© 2023. The Author(s).)

Aim: The semisynthetic derivatives MePip-SF5 and isogarcinol, which are aligned with the natural products curcumin and garcinol, were tested for their antitumor effects in a preclinical model of pulmonary melanoma metastasis., Methods and Results: MePip-SF5 was almost five times more effective in inhibiting B16F10 melanoma cell proliferation than its original substance of curcumin (IC 50 MePip-SF5 2.8 vs. 13.8 µM). Similarly, the melanoma cytotoxicity of isogarcinol was increased by 40% compared to garcinol (IC 50 3.1 vs. 2.1 µM). The in vivo toxicity of both drugs was assessed in healthy C57BL/6 mice challenged with escalating doses. Isogarcinol induced toxicity above a dose of 15 mg/kg, while MePip-SF5 showed no in vivo toxicity up to 60 mg/kg. Both drugs were tested in murine pulmonary metastatic melanoma. C57BL/6 mice ( n = 10) received 500,000 B16F10 melanoma cells intravenously. After intraperitoneal injection of MePip-SF5 (60 mg/kg) or isorgarcinol (15 mg/kg) at days 8, 11 and 14 and sacrifice at day 16, the MePip-SF5-treated mice showed a significantly ( p < 0.05) lower pulmonary macroscopic and microscopic tumor load than the vehicle-treated controls, whereas isogarcinol was ineffective. The pulmonary RNA levels of the mitosis marker Bub1 and the inflammatory markers TNFα and Ccl3 were significantly ( p < 0.05) reduced in the MePip-SF5-treated mice. Both drugs were well tolerated, as shown by an organ inspection and normal liver- and kidney-related serum parameters., Conclusions: The novel curcuminoid MePip-SF5 showed a convincing antimetastatic effect and a lack of systemic toxicity in a relevant preclinical model of metastasized melanoma.

Cluster of differentiation 24 (CD24), a mucin-like highly glycosylated molecule has been extensively studied as a cancer stem cell marker in a variety of solid cancers. The functional role of CD24 is either fulfilled by combining with ligands or participating in signal transduction, which mediate the initiation and progression of neoplasms. Recently, CD24 was also described as an innate immune checkpoint with apparent significance in several types of solid cancers. Herein, we review the current understanding of the molecular fundamentals of CD24, the role of CD24 in tumorigenesis and cancer progression, the possibility as a promising therapeutic target and summarized different therapeutic agents or strategies targeting CD24 in solid cancers. Video Abstract., (© 2023. The Author(s).)

Background: Chimeric antigen receptor (CAR) T cell therapy has shown promising results in treating blood cancers, but it has limited efficacy against solid tumors that express mesothelin (MSLN). One of the reasons is the immunosuppressive tumor microenvironment, which consists of physical barriers, multiple mechanisms of immune evasion, and various biochemical factors that favor tumor growth and survival. These factors reduce the antitumor activity of MSLN-targeted CAR T cells in clinical trials. Therefore, new therapeutic strategies are needed to enhance the effectiveness of MSLN-targeted CAR T cell therapy., Methods: To investigate whether the antitumor efficacy of anti-MSLN CAR-T cells depends on the epitopes they recognize, we generated MSLN-targeted CAR T cells that bind to different regions of MSLN (Region I, II, III and Full length). We then evaluated the antitumor activity of MSLN-targeted CAR T cells alone or in combination with the chemotherapeutic drug irinotecan or an anti-PD-1 antibody in vitro and in vivo., Results: We found that MSLN-targeted CAR T cells effectively killed MSLN-positive cancer cells (H9, H226 and Panc-1), but not MSLN-negative cells (A431) in vitro. In a mouse model of H9 tumor xenografts, all CAR T cells showed similar tumor suppression, but an MSLN-targeted scFv with Region I epitope, R47, performed slightly better. Combining irinotecan with CAR&#95;R47 T cells enhanced tumor control synergistically in both H9 xenograft mice and patient-derived xenograft mice., Conclusions: Our results suggest that irinotecan can enhance the antitumor activity of MSLN-targeted CAR T cells, and offer a promising combination therapy strategy for MSLN-positive solid tumors., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Cancer is still among the leading causes of death all over the world. Improving chemotherapy and minimizing associated toxicities are major unmet medical needs. Recently, we provided a preliminary preclinical evaluation of a human ferritin (HFt)-based drug carrier (The-0504) that selectively delivers the wide-spectrum topoisomerase I inhibitor Genz-644282 to CD71-expressing tumors. The-0504 has so far been evaluated on four different human tumor xenotransplant models (breast, colorectal, pancreatic and liver cancers)., Methods: Herein, we extend our studies, by: (a) testing DNA damage in vitro, (b) treating eight additional tumor xenograft models in vivo with The-0504; (c) performing pharmacokinetic (PK) studies in rats; and (d) evaluating The-0504 anti-tumor xenotransplant efficacy by optimizing its administration schedule based on PK considerations., Results: Immunofluorescence demonstrated that The-0504 induces foci expressing the DNA double-strand break marker γH2AX. Expression increases up to 4-fold and is more persistent as compared to free Genz-644282. In vivo studies confirmed a remarkable anti-tumor activity of The-0504, resulting in tumor eradication in most murine xenograft models, regardless of embryological origin (e.g. epithelial, mesenchymal or neuroendocrine), and molecular subtypes. PK studies demonstrated a long persistence of The-0504 in rat serum (half-life of about 40 h as compared to 15 h of the free drug), with a 400-fold increase in peak concentrations as compared to the free drug. On this basis, we reduced The-0504 administration frequency from twice to once per week, with no appreciable loss in therapeutic efficacy in mice., Conclusion: The results presented here confirm that The-0504 is highly active against several human tumor xenotransplants, even when administered less frequently than previously reported. The-0504 may be a good candidate for further clinical development in a tumor histotype-agnostic setting., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Pierpaolo Ceci and Elisabetta Falvo are inventors on patent application EP3186192B1 held by Thena Biotech that covers fusion proteins based on human ferritins and methods of use thereof. Pierpaolo Ceci is a member (free of charge) of the Scientific Advisory Committee of Thena Biotech. All the authors declare no conflict of interest., (© 2023 The Authors.)

Cancer patients with venous thromboembolism (VTE) are prone to poor prognoses. Thus, we aimed to develop a nomogram to predict the risk of VTE in these patients. We retrospectively analyzed 791 patients diagnosed with solid tumors between January 2017 and May 2021 at Tongji Hospital. Univariate logistic analysis and multivariate logistic regression were adopted in this study. Our results indicated that age ≥ 60 years, tumor stages III-IV, platelet distribution width (PDW) ≤ 12.6%, albumin concentration ≤ 38.8 g/L, lactate dehydrogenase (LDH) concentration ≥ 198 U/L, D-dimer concentration ≥ 1.72 µg/mL, blood hemoglobin concentration ≤ 100 g/dL or the use of erythropoiesis-stimulating agents and cancer types were independent risk factors. The nomogram prediction model was developed based on the regression coefficients of these variables. We assessed the performance of the nomogram by calibration plot and the area under the receiver operating characteristic curve and compared it with the Khorana score. The concordance index (C- index) of the nomogram was 0.852 [95% confidence interval (CI) 0.823 to 0.880], while the Khorana score was 0.681 (95% CI 0.639 to 0.723). Given its performance, this nomogram could be used to select cancer patients at high risk for VTE and guide thromboprophylaxis treatment in clinical practice, provided it is validated in an external cohort., (© 2023. The Author(s).)

Programmed cell death 2 (PDCD2) is related to cancer progression and chemotherapy sensitivity. The role of PDCD2 in solid cancers (excluding hematopoietic malignancies) and their diagnosis and prognosis remains unclear. The TCGA, CGGA, GEPIA, cBioPortal, and GTEx databases were analyzed for expression, prognostic value, and genetic modifications of PDCD2 in cancer patients. Functional enrichment analysis, CCK8, colony formation assay, transwell assay, and xenograft tumor model were undertaken to study the PDCD2's biological function in glioma (GBMLGG). The PDCD2 gene was associated with solid cancer progression. In the functional enrichment analysis results, PDCD2 was shown to participate in several important GBMLGG biological processes. GBMLGG cells may be inhibited in their proliferation, migration, invasion, and xenograft tumor growth by knocking down PDCD2 . Our research can provide new insights into solid cancer prognostic biomarkers of PDCD2., (© 2023 The Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co., Ltd.)

New York-esophageal cancer 1 (NY-ESO-1) belongs to the cancer testis antigen (CTA) family, and has been identified as one of the most immunogenic tumor-associated antigens (TAAs) among the family members. Given its ability to trigger spontaneous humoral and cellular immune response and restricted expression, NY-ESO-1 has emerged as one of the most promising targets for cancer immunotherapy. Cancer vaccines, an important element of cancer immunotherapy, function by presenting an exogenous source of TAA proteins, peptides, and antigenic epitopes to CD4 + T cells via major histocompatibility complex class II (MHC-II) and to CD8 + T cells via major histocompatibility complex class I (MHC-I). These mechanisms further enhance the immune response against TAAs mediated by cytotoxic T lymphocytes (CTLs) and helper T cells. NY-ESO-1-based cancer vaccines have a history of nearly two decades, starting from the first clinical trial conducted in 2003. The current cancer vaccines targeting NY-ESO-1 have various types, including Dendritic cells (DC)-based vaccines, peptide vaccines, protein vaccines, viral vaccines, bacterial vaccines, therapeutic whole-tumor cell vaccines, DNA vaccines and mRNA vaccines, which exhibit their respective benefits and obstacles in the development and application. Here, we summarized the current advances in cancer vaccines targeting NY-ESO-1 for solid cancer treatment, aiming to provide perspectives for future research., Competing Interests: Authors HZ, YM, FL, BL, DQ and MW are employed by the company Shenzhen Innovation Immunotechnology Co., Ltd. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zhou, Ma, Liu, Li, Qiao, Ren and Wang.)

Purpose: To develop and validate a user-friendly model to predict the risk of in-hospital mortality in solid cancer patients admitted to the ICU with sepsis., Methods: Clinical data of critically ill patients with solid cancer and sepsis were obtained from Medical Information Mart for Intensive Care-IV database and randomly assigned to the training cohort and validation cohort. The primary outcome was in-hospital mortality. The least absolute shrinkage and selection operator (LASSO) regression and logistic regression analysis were used to feature selection and model development. The performance of the model was validated and a dynamic nomogram was developed to visualize the model., Results: A total of 1584 patients were included in this study, of whom 1108 were assigned to the training cohort and 476 to the validation cohort. The LASSO regression and logistic multivariable analysis showed that nine clinical features were associated with in-hospital mortality and enrolled in the model. The area under the curve of the model was 0.809 (95% CI 0.782-0.837) in the training cohort and 0.770 (95% CI 0.722-0.819) in the validation cohort. The model exhibited satisfactory calibration curves and Brier scores in the training set and validation set were 0.149 and 0.152, respectively. The decision curve analysis and clinical impact curve of the model presented good clinical practicability in both the two cohorts., Conclusion: This predictive model could be used to assess the in-hospital mortality of solid cancer patients with sepsis in the ICU, and a dynamic online nomogram could facilitate the sharing of the model., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Adoptive cell therapy utilizing T cells genetically modified to express a chimeric antigen receptor (CAR) has demonstrated promising clinical results in hematological malignancies. However, solid cancers have not seen a similar success due to multiple obstacles. Investigating these escape mechanisms and designing strategies to counteract such limitations is crucial and timely. Growing evidence in the literature supports the hypothesis that radiotherapy has the potential to enhance the susceptibility of solid tumors to CAR T cell therapy, by overcoming mechanisms of resistance. Radiation treatment can increase the susceptibility of different types of solid cancers (TNBC, HNSCC, PDAC) to B7-H3 CAR T cell-mediated eradication. Multiple mechanisms, including reduced cancer cell proliferation, upregulation of the targeted antigen, modulation of apoptotic molecules may contribute to this signal. The information in the literature and the results we describesupport the ability of radiotherapy to improve the efficacy of CAR T cell therapy in solid tumors., Competing Interests: SF, XW and CRF report a patent on the B7-H3.CAR issued and licensed to Bluebird Bio. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ventin, Cattaneo, Maggs, Jia, Arya, Ferrone, Wang and Ferrone.)

Purpose: We aimed to assess the humoral response to and reactogenicity of coronavirus disease 2019 (COVID-19) vaccination according to the vaccine type and to analyze factors associated with immunogenicity in actively treated solid cancer patients (CPs)., Materials and Methods: Prospective cohorts of CPs, undergoing anticancer treatment, and healthcare workers (HCWs) were established. The participants had no history of previous COVID-19 and received either mRNA-based or adenovirus vector-based (AdV) vaccines as the primary series. Blood samples were collected before the first vaccination and after 2 weeks for each dose vaccination. Spike-specific binding antibodies (bAbs) in all participants and neutralizing antibodies (nAbs) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) wild-type, Delta, and Omicron variants in CPs were analyzed and presented as the geometric mean titer., Results: Age-matched 20 HCWs and 118 CPs were included in the analysis. The bAb seroconversion rate and antibody concentrations after the first vaccination were significantly lower in CPs than in HCWs. After the third vaccination, antibody levels in CPs with a primary series of AdV were comparable to those in HCWs, but nAb titers against the Omicron variant did not quantitatively increase in CPs with AdV vaccine as the primary series. The incidence and severity of adverse reactions post-vaccination were similar between CPs and HCWs., Conclusion: CPs displayed delayed humoral immune response after SARS-CoV-2 vaccination. The booster dose elicited comparable bAb concentrations between CPs and HCWs, regardless of the primary vaccine type. Neutralization against the Omicron variant was not robustly elicited following the booster dose in some CPs, implying the need for additional interventions to protect them from COVID-19.

The anti-cancer efficacy of anti-malignancy therapies is related to DNA damage. However, DNA damage-response mechanisms can repair DNA damage, failing anti-tumor therapy. The resistance to chemotherapy, radiotherapy, and immunotherapy remains a clinical challenge. Thus, new strategies to overcome these therapeutic resistance mechanisms are needed. DNA damage repair inhibitors (DDRis) continue to be investigated, with polyadenosine diphosphate ribose polymerase inhibitors being the most studied inhibitors. Evidence of their clinical benefits and therapeutic potential in preclinical studies is growing. In addition to their potential as a monotherapy, DDRis may play an important synergistic role with other anti-cancer therapies or in reversing acquired treatment resistance. Here we review the impact of DDRis on solid tumors and the potential value of combinations of different treatment modalities with DDRis for solid tumors., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023. Published by Elsevier B.V.)

Systemic AA amyloidosis is associated with systemic inflammatory processes such as autoimmune disorders or chronic infections. In addition, AA amyloidosis can develop in a localized or systemic form in patients with malignant neoplastic disorders, and usually involves kidneys impacting renal function. Among solid tumors, renal cell carcinoma (RCC) appears to be responsible for one-quarter to half of all cancers associated with amyloidosis. Among other solid cancers, various clinical presentations and pathological types of lung cancer and basal cell carcinoma skin were reported with AA amyloidosis more often than isolated case reports on other cancers with AA amyloidosis. Symptoms from kidney involvement rather than from the tumor per se were the presenting manifestations in cases of RCC associated with AA amyloidosis. Among hematological malignancies, clonal B cell/plasma cell dyscrasias such as monoclonal gammopathy and lymphoma were noted to be associated with AA amyloidosis. In addition, AA amyloidosis was reported in a substantial number of cases treated with immune checkpoint inhibitors such as pembrolizumab and nivolumab. The mechanism of association of cancer and AA amyloidosis seems to be mediated by the immune response exacerbated from the tumor and its microenvironment or immune therapy. The mainstay of treatment consists of therapy directed against the underlying malignancy or careful withdrawal of the offending agent. This review will discuss this rare but highly morbid clinical condition., (© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.)

Background: The recommended booster third dose of vaccination against COVID-19 in cancer patients seems reasonable to protect them against a severe disease course. A prospective study was designed to assess the immunogenicity, efficacy, and safety of COVID-19 vaccination in this cohort., Methods: Patients with solid malignancies on active treatment were followed up after the primary course and booster third dose of vaccination to assess their anti-SARS-CoV-2 S1 IgG levels, efficacy in the case of SARS-CoV-2 infection, and safety., Results: Out of 125 patients receiving the primary course of vaccination, 66 patients received a booster third dose of mRNA vaccine, with a 20-fold increase in median anti-SARS-CoV-2 S1 IgG levels compared to Ab levels six months post-primary course of vaccination ( p < 0.0001). After the booster third dose, anti-SARS-CoV-2 S1 IgG levels were comparable to healthy controls ( p = 0.113). There was a decline in Ab levels 3 ( p = 0.0003) and 6 months ( p < 0.0001) post-third booster dose. No patients had either a severe disease course or a lethal outcome in the case of SARS-CoV-2 infection after the third booster dose., Conclusion: The third booster vaccination dose against COVID-19 in solid cancer patients triggers substantial immunogenicity and is safe and effective for preventing a severe COVID-19 disease course.

Background: Opioids are widely used for patients with solid tumors during surgery and for cancer pain relief. We conducted a pan-cancer genomic analysis to investigate the prognostic features of Mu opioid receptor ( MOR ) mRNA expression across 18 primary solid cancers., Methods: All the data of cancer with MOR mRNA were retrieved from cBioPortal for Cancer Genomics. Logistic regression was used to determine the associations between MOR mRNA expression and clinicopathological features. Log-rank test and Cox regression was used for survival analysis. Subgroup analysis and propensity score matching were also carried out., Results: 7,274 patients, including 1,112 patients with positive MOR mRNA expression, were included for data analyses. Positive MOR mRNA expression was associated with more advanced stage of T (adjusted Odds ratio [OR], 1.176; 95% confidence interval [CI], 1.022-1.354; P =0.024), M (adjusted OR, 1.548; 95% CI, 1.095-2.189; P =0.013) except N (adjusted OR, 1.145; 95% CI, 0.975-1.346; P =0.101), and worse prognosis for overall survival (Hazard ratio [HR] 1.347, 95% CI 1.200-1.512, P <0.001), progression-free survival (HR 1.359, 95% CI 1.220-1.513, P <0.001), disease-free survival (HR 1.269, 95% CI 1.016-1.585, P <0.001) and disease-specific survival (HR 1.474, 95% CI 1.284-1.693, P <0.001). Patients with positive MOR mRNA expression tended to be classified as tumor microenvironment immune types II, representing low PD-L1 and low CD8A expression., Conclusion: MOR mRNA overexpression is associated with poor prognosis and poor response to PD-L1 therapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Sun, Zhuang, Cheng and Qiu.)

Objectives: This meta-analysis aimed to evaluate the association between USP39 expression, the prognosis of patients with solid cancer, and to identify the clinicopathological characteristics of these patients., Material and Method: This study was carried out using PRISMA strategy. Pubmed, ScienceDirect, Google Scholar, Ebsco, Cochrane Library electronic databases were searched for relevant studies published up to April 2022. 14 studies was included in this study. Hazard ratio (HR) and 95% confidence interval (CI) data were collected, including number of samples, detection methods, number of sample with high USP39 expression, and cut-off value. HR and 95% CI was used to evaluate the prognostic value of USP39 expression. Odds ratio (OR) with 95% CI was used to assess the effect of USP39 expression on clinicopathological parameters., Results: Qualitative analysis using 14 included studies and quantitative analysis using 7 included studies. We found that USP39 expression has significant risk for histological grade (OR 3.14, CI 95% 2.15-4.58, p<0.001), TNM stage (OR 2.23, CI 95% 1.66-3.00, p<0.001), tumor size (OR 2.17, CI 95% 1.56-3.03, p<0.001), lymph node metastasis (OR 2.31, CI 95% 1.23-4.33, p=0.009), vascular invasion (OR = 1.76, 95% CI = 1.13-2.73, p=0.01). Furthermore, high expression of USP39 protein was associated with worse OS (OR 1.17, CI 95% 1.13-1.21, p<0.001) and DFS (OR 1.39, CI 95% 1.23-1.57, p<0.001) in cancer patients., Conclusion: It can be concluded that USP39 has a significant prognostic value in patients with solid cancer and was found to have a significant relationship in the clinicopathology of solid cancer patients.

Background: A paradigm shift has occurred in cancer chemotherapy from tumor-specific treatment with cytotoxic agents to personalized medicine with molecular-targeted drugs. Thus, it is essential to identify genomic alterations and molecular features to recommend effective targeted molecular medicines regardless of the tumor site. Nevertheless, it takes considerable expertise to identify treatment targets from primary-sequencing data in order to provide drug recommendations. The Molecular Tumor Board (MTB) denotes a platform that integrates clinical and molecular features for clinical decisions., Methods: This study retrospectively analyses all the cases of discussion and decision at the MTB in Tohoku University Hospital and summarizes genetic alterations and treatment recommendations., Results: The MTB discussed 1003 comprehensive genomic profiling (CGP) tests conducted in patients with solid cancer, and the resulting rate of assessing treatment recommendations was approximately 19%. Among hundreds of genes in the CGP test, only 30 genetic alterations or biomarkers were used to make treatment recommendations. The leading biomarkers that led to treatment recommendations were tumor mutational burden-high (TMB-H) (n = 32), ERBB2 amplification (n = 24), BRAF V600E (n = 16), and BRCA1/2 alterations (n = 32). Thyroid cancer accounted for most cancer cases for which treatment recommendation was provided (81.3%), followed by non-small cell lung cancer (42.4%) and urologic cancer (31.3%). The number of tests performed for gastrointestinal cancers was high (n = 359); however, the treatment recommendations for the same were below average (13%)., Conclusion: The results of this study may be used to simplify treatment recommendations from the CGP reports and help select patients for testing, thereby increasing the accuracy of personalized medicine., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: A mathematical model of the radiation-induced cancer was devised to explain the change of incidence rates pursued by Radiation Effect Research Foundation for 25 years., Aim: The aim of this work is construction of mechanisms of radiation-induced cancer and cancers observed in the daily life., Methods and Results: First, we found a way to separate spontaneous cancers from radiation-induced cancers observed among atomic-bomb victims in Hiroshima and Nagasaki districts by using a constructed algorithm. The isolated incidence rates of radiation-induced cancers were reproduced by a two-stage model mechanical collision of impinging radiation with cells and succeeding mutation of the damaged cell to cancer. This model satisfactorily reproduced observed solid cancer incidence rates. We further attempted to construct a mathematical model for the age-dependence of spontaneous cancers appearing in the daily life and concluded that the cancer should be generated at cell division., Conclusion: With these findings, we reached to a conclusion that cancers may be suppressed by eliminating damaged cells with mild-dose radiation., (© 2022 The Authors. Cancer Reports published by Wiley Periodicals LLC.)

Background: Men with non-reproductive cancers have a discrepant outcome compared to women. However, they differ significantly in the incidence of cancer type and characteristics., Methods: Patients with single primary cancer who were 18 years or older and whose data were gathered and made accessible by the Surveillance, Epidemiology, and End Results (SEER) program were included in this retrospective analysis. Kaplan-Meier curves and Cox regression before and after propensity score matching were performed to analyze the risk survival by sex., Results: Among the 1,274,118 patients included [median (range) age, 65 year (18-85+) years; 688,481 (54.9%) male]. The median follow-up was 21 months (0-191). Substantial improvements in survival were observed for both sexes during the years of inclusion analyzed, with no difference between them, reaching a reduction of almost 17% of deaths in 2010, and of almost 28% in 2015, compared to 2004. The women had a median survival of 74 months and overall mortality of 48.7%. Males had a median survival of 30 months (29.67-30.33) with an overall mortality of 56.2%. The PSM showed a reduced difference (6 months shorter median survival and 2.3% more death in men), but no change in hazards was observed compared to the unmatched analysis [adjusted HR: 0.888 (0.864-0.912) vs. 0.876 (0.866-0.886) in unmatched]., Conclusions: The discrepancy in survival between men and women is not explained only by the incidence of more aggressive and more advanced cancers in the former., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Luz, Nascimento, Marinho, Felicidade, Antonioli, Araújo and Silva.)

Significance: Cancer-associated tissue-specific lactic acidosis stimulates and mediates tumor invasion and metastasis and is druggable. Rarely, malignancy causes systemic lactic acidosis, the role of which is poorly understood. Recent Advances: The understanding of the role of lactate has shifted dramatically since its discovery. Long recognized as only a waste product, lactate has become known as an alternative metabolism substrate and a secreted nutrient that is exchanged between the tumor and the microenvironment. Tissue-specific lactic acidosis is targeted to improve the host body's anticancer defense and serves as a tool that allows the targeting of anticancer compounds. Systemic lactic acidosis is associated with poor survival. In patients with solid cancer, systemic lactic acidosis is associated with an extremely poor prognosis, as revealed by the analysis of 57 published cases in this study. Although it is considered a pathology worth treating, targeting systemic lactic acidosis in patients with solid cancer is usually inefficient. Critical Issues: Research gaps include simple questions, such as the unknown nuclear pH of the cancer cells and its effects on chemotherapy outcomes, pH sensitivity of glycosylation in cancer cells, in vivo mechanisms of response to acidosis in the absence of lactate, and overinterpretation of in vitro results that were obtained by using cells that were not preadapted to acidic environments. Future Directions: Numerous metabolism-targeting anticancer compounds induce lactatemia, lactic acidosis, or other types of acidosis. Their potential to induce acidic environments is largely overlooked, although the acidosis might contribute to a substantial portion of the observed clinical effects. Antioxid. Redox Signal . 37, 1130-1152.

Introduction: Cancer patients are more vulnerable to coronavirus disease 2019 (COVID-19) owing to their compromised immune status. However, data regarding COVID-19 vaccine safety and immune response in cancer patients are scarce., Method: This prospective, age- and sex-matched, single-center cohort study included 61 cancer patients and 122 healthy control participants. Seropositivity was defined as anti-S IgG titer >0.8 units/ml. Primary end point was seroconversion rate of immunoglobulin (Ig)G antibodies against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein (anti-S IgG) in cancer patients vs. healthy control participants following the second dose of COVID-19 vaccine ChAdOx1 nCoV-19 (AZD1222)., Results: After the second-dose vaccination, there was no difference in seropositivity rate between groups (57 [93.44%] patients with cancer vs. 121 [99.18%] control participants; geometric mean ratio [GMR]: 0.39; 95%CI: 0.01-10.46; p -value = 0.571). In contrast, after the first-dose vaccination, the seropositivity rate was significantly lower in the cancer patients than in the control participants (50/61 [81.97%] vs. 121/122 [99.18%]; GMR: 0.07; 95%CI: 0.01-0.71; p = 0.025). The median anti-S IgG titer after the first-and second dose vaccination were not significantly different between groups. Female sex was significantly associated with a higher anti-S IgG titer. 5FU- and taxane-based chemotherapy regimens were associated with a lower IgG titer. Side effects of vaccination were tolerable., Conclusions: The anti-S IgG seropositivity rate after completing the second vaccine dose did not differ between the cancer patients and control participants. However, the anti-S IgG seropositivity rate after the first-dose vaccination was lower in cancer patients.