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

Immunomodulators, conventional immunosuppressants, and/or biologics are used more often, earlier, and longer than before in patients with inflammatory bowel disease (IBD). Along with this, the lifetime risk for cancer is estimated to be 33% in the general population in Europe. Thus, physicians face therapeutic choices in an increasing number of IBD patients with current or past malignancy. Few data are available so far for managing this IBD subpopulation and this clinical concern still remains a critical situation for four reasons: (i) risk of reactivation of dormant micrometastasis with immunomodulators is of major concern, (ii) there is a knowledge gap about the safety of the most recent molecules, (iii) current guidelines do not recommend the use of immunomodulators within 2–5 years after a diagnosis of cancer, (iv) patients with previous cancers are excluded from clinical trials. There is a lack of scientific evidence supporting the non-use of immunomodulators in IBD patients with previous cancer. Indeed, accumulative data suggest that the risk for recurrent and new cancer in patients with a history of cancer is not increased by thiopurines and anti-TNF agents. Most recently, cohort studies have found no differences in incident cancer rates in IBD patients with prior malignancy treated with vedolizumab or ustekinumab compared to those treated with anti-TNF agents. Therefore, decisions should be shared by the oncologist and the patient, considering the natural history of cancer, the time elapsed since cancer diagnosis, and IBD prognosis. Full article

Over the past 15 years, investigating the efficacy of non-invasive physical plasma (NIPP) in cancer treatment as a safe oxidative stress inducer has become an active area of research. So far, most studies focused on the NIPP-induced apoptotic death of tumor cells. However, whether NIPP plays a role in the anti-tumor immune responses need to be deciphered in detail. In this review, we summarized the current knowledge of the potential effects of NIPP on immune cells, tumor–immune interactions, and the immunosuppressive tumor microenvironment. In general, relying on their inherent anti-oxidative defense systems, immune cells show a more resistant character than cancer cells in the NIPP-induced apoptosis, which is an important reason why NIPP is considered promising in cancer management. Moreover, NIPP treatment induces immunogenic cell death of cancer cells, leading to maturation of dendritic cells and activation of cytotoxic CD8⁺ T cells to further eliminate the cancer cells. Some studies also suggest that NIPP treatment may promote anti-tumor immune responses via other mechanisms such as inhibiting tumor angiogenesis and the desmoplasia of tumor stroma. Though more evidence is required, we expect a bright future for applying NIPP in clinical cancer management. Full article

Acute myeloid leukemia (AML) is a hematopoietic malignancy characterized by altered myeloid progenitor cell proliferation and differentiation. As in many other cancers, epigenetic transcriptional repressors such as histone deacetylases (HDACs) are dysregulated in AML. Here, we investigated (1) HDAC gene expression in AML patients and in different AML cell lines and (2) the effect of treating AML cells with the specific class IIA HDAC inhibitor TMP269, by applying proteomic and comparative bioinformatic analyses. We also analyzed cell proliferation, apoptosis, and the cell-killing capacities of TMP269 in combination with venetoclax compared to azacitidine plus venetoclax, by flow cytometry. Our results demonstrate significantly overexpressed class I and class II HDAC genes in AML patients, a phenotype which is conserved in AML cell lines. In AML MOLM-13 cells, TMP269 treatment downregulated a set of ribosomal proteins which are overexpressed in AML patients at the transcriptional level. TMP269 showed anti-proliferative effects and induced additive apoptotic effects in combination with venetoclax. We conclude that TMP269 exerts anti-leukemic activity when combined with venetoclax and has potential as a therapeutic drug in AML. Full article

Background: Boron neutron capture therapy (BNCT) has been adapted to high-grade gliomas (HG); however, some gliomas are refractory to BNCT using boronophenylalanine (BPA). In this study, the feasibility of BNCT targeting the 18 kDa translocator protein (TSPO) expressed in glioblastoma and surrounding environmental cells was investigated. Methods: Three rat glioma cell lines, an F98 rat glioma bearing brain tumor model, DPA-BSTPG which is a boron-10 compound targeting TSPO, BPA, and sodium borocaptate (BSH) were used. TSPO expression was evaluated in the F98 rat glioma model. Boron uptake was assessed in three rat glioma cell lines and in the F98 rat glioma model. In vitro and in vivo neutron irradiation experiments were performed. Results: DPA-BSTPG was efficiently taken up in vitro. The brain tumor has 16-fold higher TSPO expressions than its brain tissue. The compound biological effectiveness value of DPA-BSTPG was 8.43 to F98 rat glioma cells. The boron concentration in the tumor using DPA-BSTPG convection-enhanced delivery (CED) administration was approximately twice as high as using BPA intravenous administration. BNCT using DPA-BSTPG has significant efficacy over the untreated group. BNCT using a combination of BPA and DPA-BSTPG gained significantly longer survival times than using BPA alone. Conclusion: DPA-BSTPG in combination with BPA may provide the multi-targeted neutron capture therapy against HG. Full article

Immunotherapies, including immune checkpoint blockades, play a critically important role in cancer treatments. For immunotherapies, neoantigens, which are generated by somatic mutations in cancer cells, are thought to be good targets due to their tumor specificity. Because neoantigens are unique in individual cancers, it is challenging to develop personalized immunotherapy targeting neoantigens. In this study, we screened "shared neoantigens", which are specific types of neoantigens derived from mutations observed commonly in a subset of cancer patients. Using exome sequencing data in the Cancer Genome Atlas (TCGA), we predicted shared neoantigen peptides and performed in vitro screening of shared neoantigen-reactive CD8⁺ T cells using peripheral blood from healthy donors. We examined the functional activity of neoantigen-specific T cell receptors (TCRs) by generating TCR-engineered T cells. Among the predicted shared neoantigens from TCGA data, we found that the mutated FGFR3^Y373C peptide induced antigen-specific CD8⁺ T cells from the donor with HLA-A*02:06 via an ELISPOT assay. Subsequently, we obtained FGFR3^Y373C-specific CD8⁺ T cell clones and identified two different sets of TCRs specifically reactive to FGFR3^Y373C. We found that the TCR-engineered T cells expressing FGFR3^Y373C-specific TCRs recognized the mutated FGFR3^Y373C peptide but not the corresponding wild-type peptide. These two FGFR3^Y373C-specific TCR-engineered T cells showed cytotoxic activity against mutated FGFR3^Y373C-loaded cells. These results imply the possibility of strategies of immunotherapies targeting shared neoantigens, including cancer vaccines and TCR-engineered T cell therapies. Full article

Introduction: Cancer treatment planning in older adults is complex and requires careful balancing of survival, quality of life benefits, and risk of treatment-related morbidity and toxicity. As a result, treatment selection in this cohort tends to differ from that for younger patients. However, there are very few studies describing cancer treatment patterns in older cohorts. Methods: We used data from the ASPirin in Reducing Events in the Elderly (ASPREE) trial and the ASPREE Cancer Treatment Substudy (ACTS) to describe cancer treatment patterns in older adults. We used a multivariate logistic regression model to identify factors affecting receipt of treatment. Results: Of 1893 eligible Australian and United States (US) participants with incident cancer, 1569 (81%) received some form of cancer treatment. Non-metastatic breast cancers most frequently received treatment (98%), while haematological malignancy received the lowest rates of treatment (60%). Factors associated with not receiving treatment were older age (OR 0.94, 95% CI 0.91–0.96), residence in the US (OR 0.34, 95% CI 0.22–0.54), smoking (OR 0.57, 95% CI 0.40–0.81), and diabetes (OR 0.56, 95% CI 0.39–0.80). After adjustment for treatment patterns in sex-specific cancers, sex did not impact receipt of treatment. Conclusions: This study is one of the first describing cancer treatment patterns and factors affecting receipt of treatment across common cancer types in older adults. We found that most older adults with cancer received some form of cancer treatment, typically surgery or systemic therapy, although this varied by factors such as cancer type, age, sex, and country of residence. Full article

Richter Syndrome (RS) is defined as the development of an aggressive lymphoma in patients with a previous or simultaneous diagnosis of chronic lymphocytic leukemia (CLL). Two pathological variants of RS are recognized: diffuse large B-cell lymphoma (DLBCL)-type and Hodgkin lymphoma (HL)-type RS. Different molecular mechanisms may explain the pathogenesis of DLBCL-type RS, including genetic lesions, modifications of immune regulators, and B cell receptor (BCR) pathway hyperactivation. Limited data are available for HL-type RS, and its development has been reported to be similar to de novo HL. In this review, we focus on the immune-related pathogenesis and immune system dysfunction of RS, which are linked to BCR over-reactivity, altered function of the immune system due to the underlying CLL, and specific features of the RS tumor microenvironment. The standard of care of this disease consists in chemoimmunotherapy, eventually followed by stem cell transplantation, but limited possibilities are offered to chemo-resistant patients, who represent the majority of RS cases. In order to address this unmet clinical need, several immunotherapeutic approaches have been developed, namely T cell engagement obtained with bispecific antibodies, PD-1/PD-L1 immune checkpoint blockade by the use of monoclonal antibodies, selective drug delivery with antibody-drug conjugates, and targeting malignant cells with anti-CD19 chimeric antigen receptor-T cells. Full article

Background—The purpose of this study was to investigate the bone resorption, as well as the vascular and immune microenvironment, of jaw osteosarcomas (JO) and to correlate these features with patient clinical outcomes. Methods—We studied 50 JO biopsy samples by immunohistochemical analysis of tissue microarrays (TMAs). We investigated the bone remodeling markers RANK/RANKL/OPG, the endothelial glycoprotein CD146, and biomarkers of the immune environment (CD163 and CD68 of macrophages, CD4+ and CD8+ of tumor-infiltrating lymphocytes (TILs), and an immune checkpoint PD-1/PD-L1). The biomarkers were analyzed for their influence on progression (recurrence and metastasis), overall survival (OS), and disease-free survival (DFS). Results—A strong and significant correlation has been found between CD163 staining and lower OS and DFS. The level of CD4+ and CD8+ staining was low and non-significantly associated with survival outcomes. High levels of RANK and RANKL were found in the tumor samples and correlated with lower DFS. Conclusion—Our findings suggest that CD163+ TAMs represent markers of poor prognosis in JO. Targeting TAMs could represent a valuable therapeutic strategy in JO. Full article

Background: Accurate assessment of elderly acute myeloid leukemia (AML) patients is essential before intensive induction chemotherapy and subsequent allogeneic hematopoietic stem cell transplantation. In this context, we investigated the capacity of three scores for frailty prediction. Methods: At diagnosis, 197 patients were clinically evaluated for appropriate treatment intensity. In parallel and independently, the G8-score, the Hematopoietic Stem Cell Index (HCT-CI) and the AML-score for CR were determined for each patient and analyzed with respect to overall survival (OS). Results: The G8-score and the HCT-CI were able to significantly separate “fit” from “unfit” patients, <0.001 and p = 0.008. In univariate Cox models, the predictive role for OS was confirmed: for the G8-score (HR: 2.35, 95% CI 1.53–3.60, p < 0.001), the HCT-CI (HR: 1.91, 95% CI 1.17–3.11, p = 0.009) and the AML-score (HR: 5.59, 95% CI 2.04–15.31, p = 0.001), the latter was subsequently used to verify the cohort. In the multivariate Cox model, the results were confirmed for the G8- (HR: 2.03, p < 0.001) and AML-score (HR: 3.27, p = 0.001). Of interest, when combining the scores, their prediction capacity was significantly enhanced, p < 0.001. Conclusions: The G8-, the HCTCI and the AML-score represent valid tools in the frailty assessment of elderly AML patients at diagnosis. Full article

Novel immune therapies are currently being used for patients with R/R ALL based on their ability to induce not only hematologic but also molecular remission. Despite promising results, specific clinical conditions, such as high tumor burden or extra medullary relapse, are still associated with a remarkably poor clinical outcome. Therefore, how to optimize the choice and the timing of such new treatments within different clinical settings remains a matter of debate. In addition, with the aim of increasing the rate and depth of molecular remission, clinical studies are currently evaluating the combination of these immunotherapies with chemotherapy in the contest of frontline treatment. The preliminary data suggest that this approach may increase the cure rate and perhaps reduce the use of allogeneic stem cell transplantation (alloHSCT) in first remission. In Ph-positive ALL, reproducible results are showing that frontline treatment programs, based on the combination of tyrosine kinase inhibitors and immunotherapy, can achieve unprecedented rates of hematologic and molecular remission as well as a long-term cure, even in the absence of chemotherapy and alloHSCT. The results from these studies have led to the development of potentially curative treatment modalities, even for older ALL patients who cannot be treated with conventional intensive chemotherapy. The present review examined the evidence for an appropriate use of the new immunotherapies in ALL patients and provided some appraisal of the current and future possible uses of these drugs for achieving further therapeutic improvement in the treatment of this disease. Full article

Observational and genetic studies have linked different anthropometric traits to breast cancer (BC) risk, with inconsistent results. We aimed to investigate the association between body shape defined by a principal component (PC) analysis of anthropometric traits (body mass index [BMI], height, weight, waist-to-hip ratio [WHR], and waist and hip circumference) and overall BC risk and by tumor sub-type (luminal A, luminal B, HER2+, triple negative, and luminal B/HER2 negative). We performed two-sample Mendelian randomization analyses to assess the association between 188 genetic variants robustly linked to the first three PCs and BC (133,384 cases/113,789 controls from the Breast Cancer Association Consortium (BCAC)). PC1 (general adiposity) was inversely associated with overall BC risk (0.89 per 1 SD [95% CI: 0.81–0.98]; p-value = 0.016). PC2 (tall women with low WHR) was weakly positively associated with overall BC risk (1.05 [95% CI: 0.98–1.12]; p-value = 0.135), but with a confidence interval including the null. PC3 (tall women with large WHR) was not associated with overall BC risk. Some of these associations differed by BC sub-types. For instance, PC2 was positively associated with a risk of luminal A BC sub-type (1.09 [95% CI: 1.01–1.18]; p-value = 0.02). To clarify the inverse association of PC1 with breast cancer risk, future studies should examine independent risk associations of this body shape during childhood/adolescence and adulthood. Full article

Primary and secondary malignant tumors can affect the parotid gland. The aim of this retrospective study was to evaluate the clinical features and prognosis of malignant epithelial tumors of the parotid gland. In particular, a comparison between primary and secondary cancer and survival analyses were performed. Eighteen patients with primary cancer and fifteen with intraparotid metastasis from cutaneous squamous cell carcinoma were included. A chart review was performed to collect clinical data (age, sex, smoking, alcohol consumption, tumor stage, type of surgical procedure, complications, recurrence and death). The majority of primary tumors were early (T1-2 N0, 83%) with mucoepidermoid carcinoma being the most common (33%). Secondary tumors were mostly staged P2 (53%) and N0 (67%). Subjects with secondary tumors were older than those with primary cancer. Post-operative permanent facial palsy was observed in 5 patients (17%) with primary cancer and 9 (60%) with secondary tumors (p = 0.010). Two-year overall survival for primary and secondary parotid cancer was 76.58% and 43.51%, respectively (p = 0.048), while 2-year disease-free survival was 76.05% and 38.50%, respectively (p = 0.152). In conclusion, secondary cancer of the parotid gland has worse survival than primary tumors. In the future, the implementation of multimodality treatment of intraparotid metastases is necessary to improve oncologic outcomes. Full article

Background: Even though the pre-treatment neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are well-established prognosticators in various cancers including head and neck cancers, there have been relatively few studies on the clinical significance of the post-treatment values. This study aimed to investigate the changes in NLR and PLR after concurrent chemoradiotherapy (CCRT) and to evaluate their prognostic significance in pharyngeal cancers. Methods: This study was retrospectively conducted on 461 consecutive patients with primary pharyngeal cancer who had received definitive CCRT. Blood test results before and after CCRT were obtained, and the pre- and post-treatment NLR and PLR were calculated. Patient prognosis was evaluated based on overall survival (OS) and relapse-free survival (RFS). Results: After CCRT, the NLR increased from 2.01 (interquartile range (IQR), 1.53–2.62) to 2.69 (IQR, 1.93–3.81), and the PLR increased from 118.84 (IQR, 92.61–151.63) to 193.19 (IQR, 146.28–262.46). Along with high pre-treatment NLR and high pre-treatment PLR, high post-treatment NLR was also significantly associated with worse OS and RFS (p = 0.013 and p = 0.026). In addition, patients with a high ΔNLR (i.e., the difference between pre- and post-treatment NLRs) had significantly worse OS and RFS (p = 0.013 and p = 0.026). However, only a high pre-treatment NLR (hazard ratio (HR), 2.19; 95% confidence interval (CI), 1.17–4.08; p = 0.014), age (HR, 2.16; 95% CI, 1.14–4.08; p = 0.018), and stage IV (HR, 2.11; 95% CI, 1.15–3.89; p = 0.017) were independent prognostic factors for OS in the multivariate analysis. Conclusions: In patients with pharyngeal cancers, following CCRT, the NLR and PLR increased significantly from pre-treatment values. Like the pre-treatment NLR and PLR, a high post-treatment NLR and a significant increase in NLR were also associated with poor prognosis. Further prospective studies are required to prove the independent significance of the post-treatment NLR and PLR. Full article